Relay Therapeutics, Inc. · NASDAQ:RLAY

Relay Therapeutics — AACR-NCI-EORTC Molecular Targets Conference 2021

15 slides from Relay Therapeutics's conference presentation, October 2021

  1. Slide 1: Discovery and characterization of RLY-2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα

    Discovery and characterization of RLY- 2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα Ermira Pazolli, Ph.D Relay Therapeutics, Cambridge, MA

  2. Slide 2: Authors and financial disclosures

    Ermira Pazolli1, Randy Kipp1, Alessandro Boezio1, Hakan Gunaydin1, Amanda Iskandar1, Matthew Zubrowski1, Bret Williams1, Kelley Shortsleeves1, Alexandre Larivee2, Tom McLean1, Klaus Michelsen1, Hongtao Zeng1, Jonathan LaRochelle1, Joe Manna1, Lucian DiPietro1, Mary Mader1, Bindu Bennet1, Jeremy Wilb

  3. Slide 3: Mutant PI3Kα is a validated cancer target with unrealized therapeutic potential

    Mutant PI3Kα is a validated cancer target with unrealized therapeutic potential PI3Ka is the most frequently Inhibition of WT PI3Kα leads to Multiple generations of inhibitors mutated kinase in cancer hyperglycemia Tumor cell Liver cell 25 Prior Pan-PI3K/mTOR inhibitors: 22 Significant toxicity 20 %

  4. Slide 4: Oncogenic mutations in PI3Kα are located distal to the active site

    Oncogenic mutations in PI3Kα are located distal to the active site Kinase domain mutation hotspot H1047 Catalytic site Helical domain mutation hotspots E542 and E545

  5. Slide 5: RLY-2608 binds preferentially to mutant PI3Kα at a novel allosteric site

    RLY-2608 binds preferentially to mutant PI3Kα at a novel allosteric site Faster binding to mutant vs WT Alpelisib RLY-2608 8×10 -9 1.2×10 -7 6×10 -9 8×10 -8 KD (M) KD (M) 4×10 -9 4×10 -8 2×10 -9 0 0 WT Mut Mut+Block WT Mut Mut+Block Mutant-favored binding, not impacted by blocking the orthosteric si

  6. Slide 6: RLY-2608 shows potent, mutant and isoform selective, biochemical inhibition

    RLY-2608 shows potent, mutant and isoform selective, biochemical inhibition 11,000 RLY-2608 is inactive on 50 other isoforms Biochemical mutant 10,000 45 selectivity for RLY-2608 9,000 40 8,000 35 Potency (nM) Potency (nM) 7,000 30 6,000 25 5,000 20 4,000 15 3,000 10 2,000 5 1,000 0 0 H1047R E542K E

  7. Slide 7: RLY-2608 is exquisitely selective across the kinome

    RLY-2608 is exquisitely selective across the kinome RLY-2608 inhibits only PI3Kα, with preferential inhibition of mutant

  8. Slide 8: RLY-2608 inhibits mutant PI3Kα more potently in cells

    RLY-2608 inhibits mutant PI3Kα more potently in cells Alpelisib GDC-0077 RLY-2608 50 50 50 % Inhibition pAKT S473 % Inhibition pAKT S473 % Inhibition pAKT S473 (relative to DMSO) (relative to DMSO) 25 25 (relative to DMSO) 0 0 0 MCF10A Parental MCF10A PIK3CA mutant -25 -25 -50 -50 -50 -75 -75 -100 -

  9. Slide 9: RLY-2608 potently inhibits signaling and viability in PIK3CA mutant cancer cell lines

    RLY-2608 potently inhibits signaling and viability in PIK3CA mutant cancer cell lines pAKT Viability 50 50 % Inhibition pAKT S473 (relative to DMSO) HCC1954 (H1047R) % Inhibition 0 0 T47D (H1047R) CAL33 (H1047R) -50 -50 MDAMB361 (E545K;K567R) MCF7 (E545K) HCC1428 (WT) -100 -100 10 -9 10 -8 10 -7 10

  10. Slide 10: RLY-2608 modulates pAKT in vivo

    RLY-2608 modulates pAKT in vivo % Signal pAKT S437 Exposure dependent inhibition of pAKT in tumors Plasma Unbound Concentration/Target Coverage

  11. Slide 11: RLY-2608 modulates pAKT in vivo

    RLY-2608 modulates pAKT in vivo HCC1954 HSC2 MDAMB361 MCF7 (PIK3CA H1047R) (PIK3CA H1047R) (PIK3CA E545K;K567R) (PIK3CA E545K) 150 150 150 150 % pAKT/tAKT inhibition 100 100 100 100 50 50 50 50 0 0 0 0 2 2 4 8 2 4 8 2 4 8 2 4 8 2 2 4 12 2 4 12 2 4 12 2 2 4 8 2 4 8 2 4 8 2 4 8 2 2 12 2 12 2 12 2 12 T

  12. Slide 12: RLY-2608 leads to significant tumor growth inhibition in PIK3CA mutant models

    RLY-2608 leads to significant tumor growth inhibition in PIK3CA mutant models HCC1954 HSC2 MDAMB361 MCF7 (PIK3CA H1047R; Breast) (PIK3CA H1047R; HNSCC) (PIK3CA E545K;K567R; Breast) (PIK3CA E545K; Breast) 2500 2500 2000 1500 2000 2000 1500 (Mean  SEM, mm3) (Mean  SEM, mm3) (Mean  SEM, mm3) (Mean 

  13. Slide 13: RLY-2608 has reduced impact on glucose homeostasis

    RLY-2608 has reduced impact on glucose homeostasis RLY-2608 achieves max efficacy with less Repeat dosing of RLY-2608 does not cause insulin than orthosteric inhibitors hyperglycemia in tox species 28-day repeat dose dog study Insulin levels after repeat dosing in tumor-bearing animals 200 20 150 Gl

  14. Slide 14: Conclusions

    Conclusions ▪ RLY-2608 preferentially binds mutant PI3Kα at a novel allosteric site ▪ In biochemical assays, RLY-2608 inhibits both kinase and helical domain mutant PI3Kα activity more potently than WT, and is highly selective against other PI3K family members and across the kinome ▪ RLY-2608 achiev

  15. Slide 15: Reach out with questions/comments

    Reach out with questions/comments: epazolli@relaytx.com

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