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CANCER RESEARCH TECHNOLOGY ONE NUCLEUS: RVC BIOWEDNESDAY DRUG DISCOVERY ALLIANCES July 8, 2015 ADVANCING CANCER RESEARCH TECHNOLOGY ONE NUCLEUS: RVC BIOWEDNESDAY DRUG DISCOVERY ALLIANCES July 8, 2015 ADVANCING DISCOVERIES TO BEAT CANCER

THEMES Introduction to CRT-DL and drug discovery alliances Discovery of PKCι inhibitors KIPS: Kinase THEMES Introduction to CRT-DL and drug discovery alliances Discovery of PKCι inhibitors KIPS: Kinase Identification of Proximal Substrates 2

CANCER RESEARCH UK AND CANCER RESEARCH TECHNOLOGY • CRUK is the largest fundraising medical CANCER RESEARCH UK AND CANCER RESEARCH TECHNOLOGY • CRUK is the largest fundraising medical research charity or foundation in the world • Spent ≈$550 m on research in 2014/15 • Have taken 140 new drugs into early clinical trials, leading to 9 new medicines • Funds extramural research in 70 UK universities • Supports over 5, 000 scientists, clinicians and nurses 3 • CRT develops and commercialises exciting new discoveries for patient benefit and commercial return • Exclusive rights to IP from CRUK funded research • Over 30 partnered agents in preclinical and clinical development • Returned over $30 M profit back to CRUK in 2013/4 and $75 M in total to date • HQ in London, US subsidiary in Cambridge, MA

UNPRECEDENTED ACCESS TO THE SCIENTIFIC NETWORK Unique environment and infrastructure supporting: • • • UNPRECEDENTED ACCESS TO THE SCIENTIFIC NETWORK Unique environment and infrastructure supporting: • • • Academic research Drug discovery Translational research Clinical trials Stratified medicine Aberdeen Dundee Glasgow 5 Research Institutes 15 Clinical Centres 6 Drug Discovery Units 70 Universities 1 CRT Discovery Laboratory Stirling Edinburgh Newcastle Belfast Lancaster York Manchester Liverpool Bangor Leeds Sheffield Nottingham Birmingham East Anglia Leicester Warwick Cardiff CRT has rights to all the IP generated through this network and is a single point of contact 4 Bristol Oxford Cambridge Essex Bath Southampton Exeter Sussex Francis Crick Institute Queen Mary’s Imperial College University College London Institute of Cancer Research CRT Discovery Laboratory School of Pharmacy St George’s Kings College City University Birkbeck

CRT-DISCOVERY LABORATORY CRT-DL is the in-house drug discovery unit of CRT • Located in CRT-DISCOVERY LABORATORY CRT-DL is the in-house drug discovery unit of CRT • Located in innovation hot-spots: Cambridge (Babraham) and London (LBIC) – Babraham: full drug discovery capability – LBIC: focus on target validation, protein sciences, crystallography – Discovery capability from target ID to pre-clinical candidate • ~70 staff drawn from industry and academia • Understanding biopharma needs • Translate world class research for maximum patient benefit 5

CRT-DL: AN INDUSTRY-ACADEMIA COLLABORATION LABORATORY Development Gap Publicly Funded Research Target Validation Lead Discovery CRT-DL: AN INDUSTRY-ACADEMIA COLLABORATION LABORATORY Development Gap Publicly Funded Research Target Validation Lead Discovery Academia In vivo Proof of Concept Preclinical and Clinical Development Market Patient Benefit Commercial Partners CRT Discovery Laboratories CRUK Commercial Partners • Focus on a themed area of cancer biology: overlapping research interests • Couples drug discovery engines of industry with scientific breakthroughs of academia – best of both worlds • Integrates academic PIs/KOLs into discovery research • Early buy-in from industry working as a joint discovery team • Multiple ‘shots on goal’ to deliver strongest portfolio • Flexibility, critical mass and synergies across portfolio Cancer metabolism 2010 - present Deubiquitinases in cancer Reflects broader industry trend for externalising translational research 6 2013 - present PKCι / DDR 2010 - 2015

PKCΙ: BACKGROUND • Project originated from Francis Crick Institute – Prof. Peter Parker (Protein PKCΙ: BACKGROUND • Project originated from Francis Crick Institute – Prof. Peter Parker (Protein Phosphorylation lab) – Prof. Neil Mc. Donald (Structural Biology Lab) • PKC and PKC are atypical protein kinases that belong to the PKC superfamily – Ser/Thr kinases (AGC class) • Conserved roles in establishment and maintenance of polarity • Implicated in initiation and development of many epithelial cancers – NSCLC, CRC, ovarian, PDAC – Gene amplification (3 q 26) leads to overexpression – Role in 3 D transformed cellular growth – Critical role in tumour formation, maintenance, and metastases in in vivo models – Target population for PKC inhibitors – NSCLC, m. CRC 7

LEARNINGS FROM CRT-DL ALLIANCES • At-risk work is essential to attract potential partners • LEARNINGS FROM CRT-DL ALLIANCES • At-risk work is essential to attract potential partners • Strong communication and flexibility is key – Understand the different drivers of each party – Appreciate that all sides learn from each other – Make concessions where necessary • Complementarity in execution and playing to your strengths • Joint governance process that keeps team aligned to strategic goals – Establishing strong personal relationships to drive progress/innovation – Clear set of defined objectives for the collaboration • Managing volatility within the R+D sector 8

ACKNOWLEDGEMENTS Peter Parker Neil Mc. Donald Mark Linch Philippe Riou Naren Suryavanshi Carine Rosse ACKNOWLEDGEMENTS Peter Parker Neil Mc. Donald Mark Linch Philippe Riou Naren Suryavanshi Carine Rosse Svend Kjaer Brenda Kostelecky Erik Sahai 9 The PKCι Team Gregory Ott Bruce Ruggeri Benjamin Dugan Eugen Mesaros Bruce Dorsey Mark Ator Lisa Aimone Sheila Miknyoczki Pawel Dobrzanski Thelma Angeles Steve Trusko