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o2h Discovery Brochure 2026

By mayank gupta

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https://covver.com/magazine/mayankguptao2h/o2h-discovery-brochure-2026
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Sep 1, 2026
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136

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  • an insight driven, ai enabled, co-discovery modelSeeding New Ideas... A proprietary operating system for fast tracking new ideas to a development candidate
  • Page 2WELCOME... Alchemy - From Idea to a Development Candidate..
  • Our PurposeWe @o2h have a mission to seed new ideas in life science and tech, directing our work with clear meaning. The purpose is to contribute to novel science to address unmet therapeutic need through funding, incubation, and collaborative execution. We are engaged in pre-clinical research between idea generation and the identification of a lead/development candidate, using our core strengths in chemistry, biology and technology.
  • Page 4o2h group’s vision is to be the best at seeding new ideas in life science and technology by co-investing, co-creating and co-executing across boundaries #o2hcollaborativeinnovation discovery
  • Page 5but why bother? because at o2h we love working with fearless innovators from any background with a collective passion we design and shape new discoveries that impact the world in which we live.
  • Page 6seeding new ideas by triaging funding, execution and incubation
  • Page 7What we do is supported by where we operate and our working mentality
  • Our Culture is Our IPIt is embedded in simple human values that drive our habits, reflexes and attitudes to our work, each other and our community. These 7 highlight a key piece of our human identity
  • Driving Customer SuccessIf you win, we win, and we have played our part in seeding new ideas in life-sciences, and finding patient cures… Golden rules for collaborator 1 communication
  • discovery integratedA proprietary operating system for fast tracking new ideas to a development candidate We are an insight driven multi-modality integrated drug discovert platform. A unique workflow that combines novel in-house capabilities with leading strategic partnerships embedded on an AI backbone. Our co-discovery models are customised to match your funding milestones.
  • Page 11integrated discovery
  • Page 13To take you on the journey from idea to development candidate, we have in-house capabilities comprising proprietary tools, strategic partnerships and technology platforms. We combine these with AI at each stage where appropriate, integrating human effort, hybrid tools and fully automated systems. Additionally we offer a range of business models that enhance capital efficiency, helping you to get to the lead candidate. Biology
  • idea to development candidate discoveryNovel AI Tech Partners SciFinder, Chemical.AI Deepmirror Inductivebio Ignota Labs
  • discovery collaboratorsExtensive Track Record of Collaborations in Biotech o2h discovery has supported marquee biotech and pharma across the globe since 2004. USA
  • collaborators discoveryTechBio / AI / Computational Research / Academia
  • discovery collaboratorsTechBio / AI / Computational Research / Academia
  • collaborators discoveryJapan Big Pharma / Biopharma
  • discovery collaboratorsWhat Our Customers Say... My relationship with o2h Discovery is now more than a decade. I have had many opportunities to collaborate with the o2h team for my drug discovery efforts at Karyopharm, Protai and Sporos Bioventures. I have always been impressed by their efficiency to deliver novel chemical compounds that helps to achieve targeted project milestones. Real time and insightful communication is also their key differentiator.
  • collaborators discoveryWe had a great experience working with o2h discovery on our Fragment libraries project. Their expertise in conducting fragment-based screening, targeting dual series threonine kinase on surface plasmon resonance, was impressive. The efficiency, productivity, and detailed communication from the o2h biologist team were outstanding. We look forward to further positive outcomes in our future collaborations. Eran Seger CEO and Co-founder, Protai Bio
  • discovery chemistryChemistry Capabilities We have deep chemistry expertise in medicinal chemistry, and various modalities to support a HIT ID to lead optimisation program complemented by strong HTE experience.
  • discoveryChemistry Lab Shirish Research Centre o2h discovery has launched a new state-of-the-art research centre with chemistry, biology, Scale-up, process and ADC capabilities to support integrated pre-clinical drug discovery programs.
  • Page 24discovery
  • Page 25discovery
  • incubatorHauxton Meadows Coming Soon...
  • Page 27Hauxton Meadows incubator
  • discovery integratedIntegrated Drug Discovery (IDD) Deep scientific knowledge, expert management and a thorough understanding of the drug discovery challenges
  • integrated discoveryTarget Identification & Validation Drug discovery starts with finding the right biological target and confirming that modulating it can deliver real therapeutic benefit. We have experience supporting drug discovery endeavours from inception through to pre-clinical model studies. We deploy integrated cellular, biochemical, and mechanism-based assays to confirm target relevance and disease linkage laying the groundwork for robust progression into hit discovery.
  • discovery integratedFragment Based Drug Discovery Unlock the potential of undruggable targets with o2h discovery’s Fragment-based drug discovery services
  • chemistry discoveryMedicinal Chemistry We work at the critical interface of chemistry and biology, partnering with global biotech and pharma companies to accelerate the development of innovative therapies
  • discovery chemistryADC – Different Linker Synthesis Experience We have the capabilities to design and synthesise novel ADC linkers and linker–payload architectures
  • chemistryExamples of payloads we have worked with include: discovery
  • discovery chemistryPeptide Synthesis - Capabilities and Experience A dedicated to advancing scientific research and drug discovery through exceptional peptide synthesis services
  • Page 35chemistry discovery
  • discovery chemistryNucleoside – Nucleotide Chemistry We specialise in precision synthesis of nucleoside and nucleotide analogues, backed by advanced analytics
  • chemistry discoveryHigh Throughput Experimentation (HTE) & Library Synthesis Our scientific team specialises in HTE for diverse chemistries, covering reaction screening, synthesis, purification, and library delivery
  • discovery chemistryTargeted Protein Degradation We have expertise in PROTAC services and synthesis for targeted protein degradation and integrated drug discovery o2h discovery has a customisable “off-the-shelf” PROTAC Toolbox
  • chemistry discoveryLipid Nanoparticles (LNPs) Specialising in the synthesis of diverse phospholipid molecules from mg to multi-gram scale o2h has acquired extensive expertise and capabilities to conduct the synthesis, purification and analysis of diverse and intricate lipid containing molecules, from low milligrams to multi-gram scale.
  • discovery chemistryAdvancing Next-Generation Covalent Inhibitors Harnessing Scientific Expertise and Drug-Discovery Experience to Target Complex and Intractable Diseases
  • chemistry discoveryAnalytical Chemistry Comprehensive Analytical Support Across the Entire Discovery and Development Cycle
  • discovery non-GMP Kilo-LabPR&D and Scale-up Services From lab-scale R&D to large-scale production (g to kg)
  • In-house Equipment Suite non-GMP Kilo-Lab discoveryA comprehensive range of equipment (Analytical, Reaction Technology and Purification) for ‘speed’ of project delivery:
  • discovery chemistryFrom Our Labs to the Clinic & Market The real-world impact of o2h Discovery’s scientific contributions – translating partner programmes from early chemistry into the clinic and onto the market.
  • chemistry discoveryHow we at o2hHow we at o2h leveraging Generative AILeveraging Generative AI Optimising Research, Enhancing Collaboration, &Optimising Research, Enhancing Collaboration, & Accelerating Drug Development with Generative AI.Accelerating Drug Development with Generative AI.
  • discovery chemistryIP Security – 6 Major Phases of Project Lifecycle We understand the responsibility to protect the IP of our clients during a formative stage of the process
  • chemistryGreen Chemistry Implementing eco-friendly practices from synthesis to analysis on the bench discovery
  • discovery chemistryClinical Bioanalysis & Translational Sciences An experienced scientific team supporting clinical and preclinical development programs from candidate selection through clinical proof-of concept. Supporting global partners across small molecules, peptides, biologics and emerging modalities through scientific oversight, bioanalytical strategy, study management and data driven decision support.
  • biologyNovel Biology Capabilities Advancing Next-Gen Novel Biology Capabilities @ o2h discovery
  • discovery chemistryAccelerating Non-Animal Models: A Strategic Venture Regulation, science and cost are converging. o2h and AstraZeneca are establishing a dedicated NewCo to industrialise non-animal models at speed — a co-creation model, not a vendor relationship.
  • biology discoveryDiverse Antibody Conjugate Formats An Integrated Platform for Diverse Bioconjugates and Targeted Therapeutics.
  • Page 52discovery biology/UK
  • Page 53biology/India discovery
  • discovery biologyBiology Delivered An integrated team of highly experienced biologists with a proven track record in advancing complex projects
  • Biology CapabilitiesCompound/Fragment Screening Biophysical/Biochemical and Cellular Assays biology discovery
  • discovery biologyAssay Screening We provide integrated screening services to fuel novel drug discovery programs
  • biology discoveryDrug Discovery Through Biophysical Insight Using fluorescence polarization, SPR, and thermal shift assays, we study protein binding, stability, and mechanisms
  • discovery biologyCascade Design A systematic arrangement of assays and models that progressively evaluate a compound’s efficacy, selectivity, and safety
  • biology discoveryChameLogK Assay Unveiling chameleonicity for PROTAC molecules o2h discovery; First in the World to Offer the ChameLogK Assay to our Clients...
  • discovery biologyFLIPR Penta Technology Collaborative FLIPR assay services for drug discovery programs o2h discovery’s commitment to excellence in scientific research is exemplified by our recent investment in the FLIPR Penta technology. We stand ready to collaborate seeking FLIPR-based assay services for different drug discovery programs. The introduction of the FLIPR Penta High- Throughput Cellular Screening System to our repertoire, enables rapid screening of compound libraries and to assess the effects of potential drug candidates in a fast, automated, and precise manner. It has extensive use in understanding
  • biology discoveryHigh-Content Imaging A transformative approach to drug discovery
  • discovery posterChameLogK: A Rapid, High-Throughput Assay to AssessChameLogK: A Rapid, High Throughput Assay to Assess Bioavailability of Beyond Rule of Five CompoundsBioavailability of Beyond Rule of Five Compounds 1
  • poster discoveryHigh-content analysis of DNA damage markers in multiplexed cell lines using the SemaCyte microcarrier platform Jackline Agwenge, Simon Stockwell o2h Discovery, Hauxton House, Mill SciTech Park, Cambridge CB22 5HX
  • discovery posterPoster No - ProUPS_080Poster No - ProUPS_080 Integrated drug discovery services from o2h: AdvancingIntegrated drug discovery services from o2h: Advancing therapeutic innovation through collaborative researchtherapeutic innovation through collaborative research
  • poster discoveryPoster No - ProUPS_079Poster No - ProUPS_079 An array of Targeted Degradation approaches offered as a partAn array of Targeted Degradation approaches offered as a part of integrated drug discovery services by o2h Discoveryof integrated drug discovery services by o2h Discovery
  • discoveryDMPK DMPK Capabilities o2h discovery operates a multi-modality integrated platform from Cambridge, UK, and Ahmedabad, India, with a focus on insight driven discovery.
  • DMPK discovery1. Cell-permeability, CACO2-efflux, MDCK- MDR1, MDCK-MDR1-BCRP 2. PXR, CYP induction, HepRG, HepR
  • DMPK discoveryCustomised Assays Tailored assays to meet niche research needs, including:
  • discoveryDMPK In-vivo Pharmacokinetics
  • DMPK discoveryMolecules to Medicines: Effective Pre-Formulation Extensive characterization of drug substance, formulating the NCEs for pre-clinical studies
  • discovery digitisationManage Your Integrated Drug Discovery Collaboration From Anywhere o2h.com/chemistry-in-the-cloud/ New feature
  • digitisation discoveryELN Step-by-Step A structured, end-to-end experiment record – from brief to registered material
  • discovery awardsOBN Awards 2025 o2h Discovery won the “Best Industry Support Partner of the Year” Award at OBN Awards 2025. Best Use of Technology Award
  • awards discoveryGo Beyond Award (from I SL) 2
  • discovery modelsModels Our campaign models are designed to give biotechs the head start they need to advance their drug discovery programs.
  • models models discovery o2h Biology Match Funding AwardFrom idea to milestone, start generating data on the bench Overview o2h discovery is serving up the o2h Biology Match Funding Award, an exclusive programme designed to give biotechs and big pharma an opportunity to smash through their discovery research projects!
  • discovery models o2h Kickstarter AwardA competitive award to turbocharge your biotech startup with a chemistry boost! 8+
  • models discoveryMeet the Kickstarter Winners Since its launch, the o2h Kickstarter Award has supported innovative biotech companies and academic spinouts from around the world, helping them generate critical scientific data and reach their next milestone.
  • discovery modelsThe o2h Kickstarter: Peptide The o2h Kickstarter: Peptide
  • models discovery o2h Plug-in Biotecho2h Plug-in BiotechA new plug-and-play model for structuring a biotechA new plug-and-play model for structuring a biotech OverviewOverview o2h Discovery has launched o2h Plug-in Biotech, a newo2h discovery has launched o2h Plug-in Biotech, a new dedicated service designed to help early-stage biotechdedicated service designed to help early-stage biotech companies establish and scale subsidiary-like operationscompanies establish and scale subsidiary-like operations in the UK and India.in the UK and India.
  • discovery models o2h Discovery Platinum PartnerAn exclusive benefit that helps you deliver more value to your portfolio About
  • models discoveryA Match Funding Offer to Support CriticalA Match Funding Offer to Support Critical Proof-of-Concept StudiesProof-of-Concept Studies Unlock high value ideas, assets and near misses... Unlock high value ideas, asset and near misses
  • Page 84discovery models
  • Page 85models discovery
  • kickstarter winners o2h Kickstarter Winners’ WallOver the years, we have become a trusted discovery partner to early-stage life science, biotech, and techbio companies, helping them translate innovative ideas into meaningful scientific progress and successful funding outcomes. USA
  • winners kickstarterUK & Europe Molecular Glue Labs
  • venturesA passion for investing We have a track record of nurturing and investing in emerging life science and tech companies.
  • The o2h Human Health Funds venturesAbout us Founded in 2018, o2h Ventures is a UK-based venture capital firm focused on investing in the next generation of biotech companies that are working to improve human health. Headquartered in Cambridge, o2h Ventures has invested over $10 million into more than 35 early-stage life science companies, with a particular focus on novel therapeutics and emerging technologies like AI and machine learning.
  • venturesCambridge The UK’s Billion-Pound Biotech Engine
  • Access: The o2h advantageBeing part of Cambridge’s biotech network gives us a unique window into tomorrow’s science. Unlike traditional funds that only see deals once they are in the market, we are embedded within the biotech ecosystem itself. Through o2h Ventures and o2h Discovery, we see science earlier, support founders at inception, and build trusted relationships long before others. d deals screened annually
  • venturesPortfolio Evolution Across Key Milestones Therapeutics
  • venturesPlatform Biotech Proof of concept
  • Molecular Glue Labs venturesDiscovery Pre-clinical
  • venturesThe Integrated o2h Biotech Engine From proprietary deal access to Big Pharma exit, o2h Ventures uniquely integrates discovery, incubation, community, and capital—de-risking early-stage science and creating outsized opportunities in biotech.
  • venturesBiotech Finance Across the Lifecycle o2h Ventures supports biotech companies through every stage, from inception to scale. Our SEIS fund provides early, tax-efficient capital to university spin-outs and founders, alongside mentorship and access to our Cambridge network. The Knowledge-Intensive EIS Fund offers follow-on capital to drive clinical and commercial growth. As our portfolio matures, the Seven Sisters Human Health Growth Fund backs de-risked, later-stage biotech companies ready to scale. Inflexion point
  • venturesPortfolio Overview - Clinical Company
  • venturesPortfolio Overview - Pre-Clinical Company
  • venturesCompany Portfolio Overview - Pre-Clinical
  • venturesPortfolio Overview - Pre-Clinical Company
  • venturesPortfolio Overview - Tech Bio Company
  • ventures o2h ChaiTime Portfolio Pitch DaysThe o2h chaitime portfolio pitch day introduces a new format to our chaitime series, transitioning to an in-person event with a simultaneous webinar. It is designed to foster collaboration, create investment opportunities, and facilitate the exchange of innovative healthcare ideas within a global investor network. This event serves a dual purpose: Connecting o2h Ventures’ portfolio companies with biotech investors worldwide and providing a platform for these portfolio companies to showcase their potential, interact with experienced investors, and build a potential pipeline for their funding round.
  • technologyWe partner with accelerators, incubators and seed stage companies to support their digital transformation journey through all phases of software development services including planning, design, development and implementation life science The o2h team are leaders in the biotech community and have been actively involved as investors, service providers, and holding various board positions. We have been engaged in grassroots scientific activity for over 20 years.
  • technologyOur Services We have developed and launched 50+ projects across web and mobile applications
  • technology modelsTech Kickstarter Competition Give your startup a tech boost…
  • models technologyIdentifying and Executing Quick-Win Generative & Agentic AI Use Cases in Life Sciences About Polaris o2h has been working at the intersection of technology and life sciences for over two decades, supporting both large pharmaceutical companies and emerging biotechs across discovery, technology, and AI/digital transformation projects.
  • technology case studyRevolutionising Genetic Engineering with Version Control Solutions Industry: Biotechnology
  • case study technologyTransforming Museum Experiences with AI Industry: Arts, Culture (EdTech)
  • technology collaboratorsExtensive Track Record of Collaborations in Tech Over the years we have provided tech expertise to many companies in life science, AI/tech and green innovation.
  • Page 111collaborators technology
  • incubator a lively community of creatorsShaping one of the region’s most exciting community of entrepreneurs in life science, and technology
  • Page 113incubator i n c u b a t o r the mill scitech park o2h incubator operates the mill scitech park in Hauxton, Cambridge, a place for entrepreneurs, scientists, techies & dreamers. Supported by high specification labs to create a genuinely unique environment for creativity and innovation to thrive. We are quite obsessive about playing our part in the creation of a global collaborative community around innovation because we believe it’s the cross fertilisation of ideas across boundaries that spurs exciting new ideas, and well, we just can’t help doing what we love.
  • incubatorHauxton House a studio style workspace for life scientists & techies An incubation model like no other
  • Page 115Hauxton House incubator
  • incubatorHauxton House
  • Page 117Hauxton House incubator
  • communityBuilding a Community o2h is a community-aware company working with organisations on a wide range of programs. We connect scientists, entrepreneurs, and society through initiatives from planting 100,000 trees to hosting Women’s Open Day, Influencer Bootcamps, Biotech Bikers and Cambridge Wide Open Week. By opening our doors to investors, innovators, students, and residents, we help shape the future of science with the community.
  • communityThe Cambridge TechBio Caucus An experimental caucus to learn how we can nurture the world leading techbio space in Cambridge...
  • community we are absolutely delighted to launch the influencer bootcampsHauxton House, Mill Scitech Park, Cambridge o2h incubator organises two influencer bootcamps events per year, one covering life sciences and one covering tech. Looking far beyond the ‘start-up’ skills the idea is to bring together a group of people who we call the ‘Dirty Dozen’, who are proven in getting their hands dirty helping the British tech economy flourish. We try to nurture a vibe that is an intimate space for exchange of thoughts and not a typically rigid classroom/panel/ conference format where you are only expected to only listen. We hope that the dirty dozen tackle subjects in depth, disagree and stir up a little controversy! We cover a range of subjects from economic landscape, strategy, creativity, technology trends, customers/ investors, deals/exits, the role of Cambridge but more importantly we allow for personal stories, workshops, debate and masterclasses. The invites include influencers covering from the quintet of (1) Small co technical experts and CXOs, (2) Big co’ Managers/Executives, (3) Academia/ Profs, (4) Policy Makers and (5) Incubators & Seed/VCs.
  • communityA drop-in open conversation with Coffee, Masala Chai & Sandwiches The AIM (Accelerator, Incubator, Mentoring) squad is a no agenda highly casual meeting held every quarter at the o2h incubator on subjects we care to talk about over masala chai, sandwiches and coffee. This is not an event where the invite is based on seniority, neither is it invite only, so we share with any colleagues who we think are like minded even if they are new to our line of work, we want to be inclusive and open to all experience levels.
  • communityCambridgesquared TM
  • Page 123community
  • communityAccessing Public Market Liquidity Inside High-Density Ecosystems The Cambridge Stock Exchange Project is creating a platform for private companies who are scaling up to access liquidity from the market inside in the UK.
  • communityThe CSEP Funding Continuum The CSEP Funding Continuum is a long-term roadmap connecting UK science and technology companies with capital providers, exchanges, and institutional partners — from grant funding through to public markets.
  • communityA WEEK OF LIFE SCIENCES @ THE HOME OF LIFE SCIENCES
  • communitySUPPORTING INCLUSIVE COLLABORATION In March 2023, the government published its new strategy to make the UK a science and technology superpower by 2030. The plan draws on industry, finance, academia and civil society to realise its ambition. Cambridge has long championed collaboration, establishing itself as one of the leading science and technology clusters in the world. A reputation built on world-leading innovation, fast-growing science and tech companies, academia, and innovation centres - underpinned by investment, people and skills. To support and further progress this world-leading position requires inclusive collaboration across the Cambridge community.
  • Page 128CWOW 2026 SCHEDULE - WHAT'S ON! THURSDAY 11TH JUNE
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  • communityEXPLORE THE CITY’S LIFE SCIENCES ECOSYSTEM IN ONE DAY!
  • Page 131community
  • communityDriving Net Zero: ESG-Driven Tree Planting Surpasses 100K Milestone... o2h group encourages contribution, partnerships and connections with local NGO’s and the community
  • communityInspiring Scientific Curiosity: Lab workshops for young locals
  • Page 134we believe to build a company we first build our culture
  • an insight driven, ai enabled, co-discovery modelInsight-Driven Science State-of-the-art research centres in Cambridge, UK and Ahmedabad, India
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discovery poster

ChameLogK: A Rapid, High-Throughput Assay to AssessChameLogK: A Rapid, High Throughput Assay to Assess Bioavailability of Beyond Rule of Five CompoundsBioavailability of Beyond Rule of Five Compounds

1,2 e StaceCatherine StaceDharmesh BhattDharmesh Bhatt, Andy Morley , Claudio Dagostin, Andy Morley , Claudio Dagostin, Mayank Gupta , Pranav Pandya, Mayank Gupta , Hardic Dave, Pranav Pandya, Dhruv Lad, Hardic Dave, Vinkal Zalavadia, Dhruv Lad , Vinkal Zalavadia, Vishal Patel , Hemal Soni, Vishal Patel, Nilesh Dagia, Hemal Soni, Sunil Shah, Nilesh Dagia, Prashant Shah, Sunil Shah , Prashant Shah

overy Pvt. Ltd., Changodar, Ahmedabad, India.o2h Discovery Pvt. Ltd., Changodar, Ahmedabad, India.o2h Ltd., Mill SciTech Park, Hauxton, Cambridgeshire, UK.o2h Ltd., Mill SciTech Park, Hauxton, Cambridgeshire, UK.* Correspondence to [email protected]* Correspondence to [email protected] act Abstract

LogKChameLogK is a cutting-edge method for measuring chameleonicity, a vital factor in assessing cell permeability propensity of small molecules, includingis a cutting edge method for measuring chameleonicity, a vital factor in assessing cell permeability propensity of small molecules, including d Rule‘Beyondof Five’Rule-of-such asFive’PROTACs,such as PROTACs, macrocycles and peptides. Chameleonicity is ability of molecules to conformationally adapt to their environment,macrocycles and peptides Chameleonicity is ability of molecules to conformationally adapt to their environment, IAM

IAM by intramoleculardriven by intramolecular hydrogen bonds; ChameLogK combines lipophilicity (BRlogD) and polarityhydrogen bonds ChameLogK combines lipophilicity (BRlogD) and polarity (Δlog kw

(Δdescriptorslog kw

) descriptors. Leveraging literature methods,Leveraging literature methods, s developedo2h has developed a reliable, high-throughput platform to rapidly and inexpensively measure chameleonicity, accelerating optimization of Beyond Rule-of-a reliable, high throughput platform to rapidly and inexpensively measure chameleonicity, accelerating optimization of Beyond Rule of erapeuticFive therapeutic compoundscompounds meleonicity: An indicator of bioavailability and cellChameleonicity: An indicator of bioavailability and cell

Assay Validation and Platform DevelopmentAssay Validation and Platform Development permeability for Beyond Rule of Five moleculespermeability for Beyond Rule of Five molecules o2h conducted a rigorous validation process, with a variety of different chemicalo2h conducted a rigorous validation process, with a variety of different chemical eleonicity is the capacity of aChameleonicity is the capacity of a ule to hide polarity in nonmolecule to hide polarity in non-polarpolar nments and expose it in water,environments and expose it in water, chieving sufficient permeabilityhelp achieving sufficient permeability olubility for drug molecules withand solubility for drug molecules with olecular weight [1]high molecular weight [1]

species, underscoring the reliability of the assay as a robust and transferable platform,species, underscoring the reliability of the assay as a robust and transferable platform, broadly applicable for multiple drug discovery programs.broadly applicable for multiple drug discovery programs.

Validated with >20 different compounds, including macrocycles, nonValidated with >20 different compounds, including macrocycles, non-macrocyclicmacrocyclic compounds, and PROTACscompounds, and PROTACs >100 compounds examined to date confirm versatility and effectiveness in designing>100 compounds examined to date confirm versatility and effectiveness in designing bioavailable compounds beyond Ro5 constraintsbioavailable compounds beyond Ro5 constraints

Adapted from DanielusAdapted from Danieluset al, Nature 2020 [2] et al, Nature 2020 [2]

A any years, it has been known that bRo5 molecules, such as macrocycles and smallFor many years, it has been known that bRo5 molecules, such as macrocycles and small

B es, can exhibit chameleonic propertiespeptides, can exhibit chameleonic propertiesconformational flexibilityconformational flexibility - driven by thedriven by the tion of intramolecular hydrogen bondsformation of intramolecular hydrogen bonds [3][3]

ompounds often suffer from a poor permeability and bioavailability profile.bRo5 compounds often suffer from a poor permeability and bioavailability profile. sign and optimization of compounds with chameleonicThe design and optimization of compounds with chameleonic rties is central toproperties is central to optimizing solubility and permeability [4]optimizing solubility and permeability [4]

IAM

IAM

D, Δlog kBRlogD, Δw and ChameLogK are threelog kw and ChameLogK are three ementary measures revealing lipophilicity,complementary measures revealing lipophilicity, lity, exposed polarity, and chameleonic masking;solubility, exposed polarity, and chameleonic masking; er forming a triad of drugtogether forming a triad of drug-likeness, guidinglikeness, guiding er compound prioritization by explainingsmarter compound prioritization by explaining ability and bioavailability [5]permeability and bioavailability [5]

Figure 1: A. Output data showing correlation of Log K’ with % acetonitrile for a PROTAC andFigure 1: A. Output data showing correlation of Log K’ with % acetonitrile for a PROTAC and a classic Ro5 compound;a classic Ro5 compound;B. Summary of chameleonicity across a range of chemical speciesB. Summary of chameleonicity across a range of chemical species o2h has streamlinedo2h has streamlined

Results

Results processes for processes for PROTACs: Displayed distinct “Chameleonic” qualities.PROTACs: Displayed distinct “Chameleonic” qualities.maximal throughputmaximal throughput establishedOther established phys chem measures relating to permeability, such as ePSA [6][1] arephys chem measures relating to permeability, such as ePSA [6][1] are aratively low throughput and costly, revealing a need for an easilycomparatively low throughput and costly, revealing a need for an easily-accessibleaccessible and productivityand productivity

Non macrocyclesNon-macrocycles: Moderate chameleonicity, showingModerate chameleonicity, showing ative measure to support rapid design and optimization of bRo5 compoundsalternative measure to support rapid design and optimization of bRo5 compounds expected flexibility compared to classic Ro5 and PROTACsexpected flexibility compared to classic Ro5 and PROTACscreating a cost-creating a cost- Macrocycles: Led by Cyclosporin, showed variable behaviourMacrocycles: Led by Cyclosporin, showed variable behavioureffective and easy-effective and easy- [5] and hasE3 Ligands: Consistent behaviour, possibly involving internalE3 Ligands: Consistent behaviour, possibly involving internalaccess version of thisaccess version of this ameLogK method was pioneered in byThe ChameLogK method was pioneered in by GiuliaGiulia Caron’s group in TurinCaron’s group in Turin[5] and has ground breakingground-breaking folding or interactionsfolding or interactions red significant interest in the academic settinggarnered significant interest in the academic setting, but had not been developed into, but had not been developed into technique

Ro5 moleculesRo5 molecules like caffeine, and diazepam defied expectationlike caffeine, and diazepam defied expectation technique transferable platform for routine screening in the commercial settinga fully-transferable platform for routine screening in the commercial setting scovery is the first in the world to offer the ChameLogK assay to clients too2h discovery is the first in the world to offer the ChameLogK assay to clients to rt their drug discovery programssupport their drug discovery programs

Supporting a range of modalitiesSupporting a range of modalities

Measuring ChameLogK: How it worksMeasuring ChameLogK: How it works

The increasing need to explore the bRo5 spaceThe increasing need to explore the bRo5 spaceto access novel chemistry, betterto access novel chemistry, better mechanisms of action, and exciting new modalities, requires a way to quickly andmechanisms of action, and exciting new modalities, requires a way to quickly and inexpensively measure chameleonicityinexpensively measure chameleonicity

LogK is the difference (ChameLogK is the difference (Δlog k′) between theΔlog k′) between the ental retention at 100%experimental retention at 100% MeCN on a PLRP-SMeCN on a PLRP S , and the extrapolated retention at 100%column, and the extrapolated retention at 100% MeCNMeCN d from the linear region measured atobtained from the linear region measured at 0% MeCN50/60/70% MeCN. Positive values indicate extra. Positive values indicate extra on in the nonretention in the non-polar limit, consistent withpolar limit, consistent with masking/folding (i.e. chameleonicity).polarity masking/folding (i.e. chameleonicity).

d features:Method features: based method, using PLRPHPLC-based method, using PLRP-S columnS column rd the retention time (RT) of compound inRecord the retention time (RT) of compound in ring ratios ofdiffering ratios of water:acetonitrilewater:acetonitrile r regression to fit of Log k' PLRPLinear regression to fit of Log k' PLRP-S and the %S and the % nitrile; Chameleonic properties are observedacetonitrile; Chameleonic properties are observed teeper downward slope with an upas a steeper downward slope with an up-ticktick polate to calculate at 100% acetonitrile andExtrapolate to calculate at 100% acetonitrile and late Chamelogkcalculate Chamelogk using the formula:using the formula: melogk = Exp. log k' 100Chamelogk = Exp. log k' 100 - Ext. log k' 100Ext. log k' 100

This assay represents aThis assay represents asignificant step forwardsignificant step forwardin assessing molecules such asin assessing molecules such as PROTACs and optimization of their properties [7] Enabling:PROTACs and optimization of their properties [7] Enabling:

Hetero bifunctionals

Glues

Optimization to fit with target biology; e.g. crossingOptimization to fit with target biology; e.g. crossing

Heterothe BBB or efficiently accessingthe BBB or efficiently accessingintracellular targetsintracellular targetsPeptides bifunctionals

Characterization of molecules to guideCharacterization of molecules to guidedesign and design and create a robust pre-clinical data packagecreate a robust pre-clinical data package Understand theGlues

Understand therelationship between biophysicalrelationship between biophysicalMacrocycles and cell-basedand cell-basedresults results

Peptides

Macrocycles

A key part of your drug discovery programA key part of your drug discovery program o2h offers the o2h offers the ChameLogK assay as partChameLogK assay as part of a comprehensive suite of ADMET andof a comprehensive suite of ADMET and assay biology, eassay biology, enabling fullnabling full characterisation of compoundscharacterisation of compounds

Graphics adapted from [2] and [5]Graphics adapted from [2] and [5]

o2h also offers a range of integratedo2h also offers a range of integrated services linking directly to this field:services linking directly to this field:

ReferencesReferences l (2021) ‘Prediction of Chameleonic Efficiency’,[1] David et al (2021) ‘Prediction of Chameleonic Efficiency’,ChemMedChem 16(7), pp2669ChemMedChem 16(7), pp2669-26852685 et al, (2020) ‘[2] Danielas et al, (2020) ‘Solution Conformations Explain the ChameleonicSolution Conformations Explain the Chameleonic BehaviourBehaviour of Macrocyclic Drugs’,of Macrocyclic Drugs’,Nature 26(23), pp5231Nature5244 26(23), pp5231-5244 nd Lokey, (2017) ‘Chapter 5:[3] Bockus and Lokey, (2017) ‘Chapter 5:Bioactive and MembraneBioactive and Membrane-Permeable Cyclic Peptide Natural Products’,Permeable Cyclic Peptide Natural Products’,Practical Medicinal Practical Medicinal ith Macrocycles: Design, Synthesis, and Case Studies,Chemistry with Macrocycles: Design, Synthesis, and Case Studies,John Wiley and Sons, Inc.John Wiley and Sons, Inc. et al, (2023), ‘Cell[4] Ramelotpermeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design,et al, (2023), ‘Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design, ion in Structural Biology 80, p102603Current Opinion in Structural Biology 80, p102603 enez et al (2023), ‘[5] Garcia Jimenez et al (2023), ‘Chamelogk: A ChromatographicChamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-Chameleonicity Quantifier to Design Orally Bioavailable Beyond Rule ournal of Medicinal Chemistry 66(15), p10681.of-5 Drugs’, Journal of Medicinal Chemistry 66(15), p10681.Seminal article by Giulia Caron’s groupSeminal article by Giulia Caron’s group al (2014), ‘EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides’,[6] Goetz et al (2014), ‘EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides’, al Chemistry Letters, 5(10).ACS Medicinal Chemistry Letters, 5(10). t al (2024), ‘Exploring the chemical space of orally bioavailable PROTACs’, Drug Discovery Today 29(4), p103917.[7] Apprato et al (2024), ‘Exploring the chemical space of orally bioavailable PROTACs’, Drug Discovery Today 29(4), p103917.

PROTACs: off PROTACs:the shelf toolbox, featuring >100 buildingoff-the-shelf-toolbox, featuring >100 building blocks, a range of E3 ligands and readyblocks, a range of E3 ligands and ready-to-use linkersto use linkers Custom Peptide SynthesisCustom Peptide Synthesis: parallel and solid & solution: parallel and solid & solution phase; ‘peptide guarantee’phase; ‘peptide guarantee’ Macrocycles and natural product chemistryMacrocycles and natural product chemistry Molecular gluesMolecular glues, with comprehensive assay suite for in, with comprehensive assay suite for incell target engagement and degradationcell target engagement and degradation Medicinal and syntheticMedicinal and syntheticchemistry chemistry nt to learn more about this assayWant to learn more about this assay

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