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22 MAT2A MAT2A Inhibition is Synthetic Lethal with MTAP Deletion Strategies to address MTAP-/- Prevalence in ~15% of all Solid Tumors MTAP-MAT2A Synthetic Lethality Biology MTAP Methionine MAT2A is key enzyme that produces SAM in cells MTAP deletion leads to MTA accumulation MAT2A MAT2A inhibitor MTA accumulation partially inhibits PRMT5 MTA MTA PRMT5 Inhibition of MAT2A results in reduction of SAM, starving PRMT5 of its substrate MTA Endogenous Suppression in MTAP-/- PDX Models AMGEN® Methylation Pathway Suppression in MTAP(-/-) Squamous Lung (LUSC) SDMA Effect Size (PDX Tissue Microarray) Full Cohort MTAP(-/-) Fraction -log10(pval) 6- 4- 2- LUSC LUSC 300- Nuclear SDMA H-score 200₁- 100)- p-value <0.0001 0. MTAP wt n=44 MTAP (-/-) n=12 Histology 2 no sig. diff. ° Protein Methylation SAM Loss of methylation function of PRMT5 results in defects in RNA splicing, gene expression and genome integrity 0- Histology 2 -0.25 0.00 0.25 Effect Size 0.50 0.75 1.00 IDEAYA Data: AACR 2023 (M. Fischer et al.) - Volcano plot comparing nuclear SDMA H- Score by IHC in MTAP(-/-) relative to MTAP wt across tissue microarray (TMA) of treatment-naïve PDX models; LUSC shows most significance effect across tumor histologies Nuclear SDMA H-score 300 200- 100 - 0 - MTAP wt n=13 MTAP (-/-) n=6 IDEAVA BIOSCIENCES

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