Investor Presentaiton

36 Polymerase Theta (Pol Theta) Synthetic Lethality Program Pol Theta GSK Potential First-in-Class Helicase Inhibitor is Synthetic Lethal to HR and NHEJ Perturbation Role of Pol Theta in Tumor Biology Pol Theta is an error-prone multi-domain protein with helicase / polymerase activities ATPase domain RAD51 binding sites Polymerase domain Pol Theta DNA break end-joining is critical when canonical repair pathways fail Pol Theta Inhibitor Drug Discovery Discovered Pol Theta inhibitors with IC50 <10 nM in biochemical assays against Pole Drug-like properties of Pole inhibitors support oral dosing in humans Pol Theta Inhibitor Synergy in HRD Pol Theta inhibition is synthetic lethal with PARP inhibition in HR-deficient cancer cells Synergy mapped to D-R (HSA) Combination of PolQi and PARPI 100 Poor NHEJ Substrates Excessive Resection Aborted HR Theta Mediated End-Joining Pol e Microhomology Mediated End-Joining D. Wyatt et al. Mol Cell (2016) Intra- and Inter- Chromosomal Templated Insertions (MMBIR-like) % Control 50 50 IDEAYA / GSK Data Polei Niraparib Antagonism Synergy IDEAVA BIOSCIENCES

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