Blossomhill Therapeutics, Inc. · NASDAQ:BLSM
Blossomhill Therapeutics — AACR Symposium
13 slides from Blossomhill Therapeutics's conference presentation
Slide 1: Discovery and characterization of BH-501284: A non-covalent, pan-KRAS inhibitor
Discovery and characterization of BH-501284: A non-covalent, pan- KRAS inhibitor for treatment of diverse KRAS-mutant tumors Nancy Ling, Evan Rogers, Eugene Rui, Wei Deng, Ping Jiang, Zhenping Wang, Yue Hu, Joshua Choi, Danan Li, Anindya Sarkar, Levan Darjania, Geoffrey Oxnard, Jean Cui BlossomHill
Slide 2: Disclosure Information
Disclosure Information Jean Cui, Ph.D. I have the following relevant financial relationships to disclose: ▪ Co-founder and Employee of BlossomHill Therapeutics, Inc. ▪ Stockholder in BlossomHill Therapeutics, Inc.
Slide 3: Targeting oncogenic KRAS mutations
Targeting oncogenic KRAS mutations • KRAS mutations are the most frequent oncogenic driver alterations found in cancer • Covalent KRAS G12C inhibitors are now FDA approved to treat KRAS G12C mutant NSCLC & CRC • Investigational KRAS inhibitors leverage several emergent design approaches, including n
Slide 4: Challenges beyond KRAS G12C inhibitors
Challenges beyond KRAS G12C inhibitors • The Switch-II pocket is shallow such that non-covalent inhibitors often require high molecular weight, resulting in unfavorable drug-like properties which can impair oral bioavailability • A fresh chemical scaffold will be needed to deliver a pan-KRAS Switch-
Slide 5: KRAS Switch-II inhibitors rigidify KRAS conformation to disable binding with effectors
KRAS Switch-II inhibitors rigidify KRAS conformation to disable binding with effectors The induced Switch II allosteric pocket is available A potent Switch-II inhibitor can achieve dual state in both GTP-bound (on) and GDP-bound (off) KRAS binding (“On” / “Off”) through an induced and rigidified KRA
Slide 6: BH-501284: A pseudo-irreversible pan-KRAS inhibitor with long residence and tight binding
BH-501284: A pseudo-irreversible pan-KRAS inhibitor with long residence and tight binding Nucleotide Exchange Assay (NEA) Surface Plasmon Resonance(SPR) Assay • Potent inhibition of the SOS1-mediated • Picomolar binding affinity, significantly tighter than KRAS bound GDP to GTP exchange with AMG410
Slide 7: Fast and deeply modulated active KRAS::RAF interaction and sustained blocking of KRAS signaling
BH-501284 fast and deeply modulated active KRAS::RAF interaction and sustained blocking of KRAS Signaling GP2D (KRAS G12D) Fast Inhibition of KRAS::RAF Association GP2D Cells: Compounds @ 1 μM 30 120 % of DMSO Control 100 BH-501284 pERK-HTRF (% of Control) 20 KRAS::RAF 80 Zoldonrasib 60 10 40 20 0 0
Slide 8: BH-501284 demonstrated high potency in KRAS mutant cells sparing HRAS and NRAS
BH-501284 demonstrated high potency in KRAS sparing HRAS and NRAS Median cell viability IC50 0.81 nM in 41 KRAS G12/G13 Cellular pERK Inhibition 10000 mutant cells excluding KRAS G12R Activity IC50 (nM) 1000 pERK Inhibition Median IC50 (nM) 100 10 RAS Mutation pERK (N) Cell Viability (N) 1 KRAS G12V
Slide 9: BH-501284 demonstrated marked efficacy in KRAS mutant mouse tumor models
BH-501284 demonstrated marked efficacy in KRAS mutant mouse tumor models BH-501284 showed dose BH-501284 achieved deep tumor regression at low dose levels (5-15 mg/kg BID) dependently increased exposures in mice H441 (NSCLC: KRAS G12V) RKN (LMS: KRAS G12V) SW620 (CRC: KRAS G12V) 2000 2500 PK of BH-5
Slide 10: BH-501284 achieved marked efficacy comparable to covalent KRAS G12Ci divarasib
BH-501284 achieved marked efficacy comparable to covalent KRAS G12Ci divarasib • In wash-off experiment, BH-501284 sustained pERK inhibition as effectively as divarasib, a covalent KRAS G12Ci, while AMG410 lost pERK inhibition • In a KRAS G12C tumor model, BH-501284 induced tumor regression at a low
Slide 11: BH-501284 achieved tumor regression at low dose levels compared with clinical compounds
BH-501284 achieved tumor regression at low dose levels compared with clinical compounds • BH-501284 achieved deep tumor regression in H441 KRAS G12V tumor model at significantly lower dose levels than reported Switch-II Inhibitors BH-501284 JAB-23E73 BBO-11818 NCI-H441 (KRASG12V) NCI-H441 (KRASG12V)
Slide 12: Evaluation of BH-501284 in combination with cetuximab
Evaluation of BH-501284 in combination with cetuximab • Addition of EGF ligand (40ng/mL) reduced KRAS inhibitor • Combination of BH-501284 with potency in MiaPaca (PDAC: KRAS G12C) cell lines cetuximab prolonged the inhibitory effect on LS180 (CRC: KRAS G12D) 150 150 cell growth pERK activity (vs DM
Slide 13: Summary
Summary BH-501284 is a potent pseudo-irreversible dual- state pan-KRAS inhibitor, sparing H/NRAS • High binding affinity with prolonged residence time (>54 hrs) • Superb cell potency (low nM) with sustained inhibition against KRAS G12V/D/C, sparing H/NRAS • Marked efficacy in multiple KRAS mutated m