Bridgebio Oncology Therapeutics, Inc. · NASDAQ:BBOT
Bridgebio Oncology Therapeutics — ENA 2024
19 slides from Bridgebio Oncology Therapeutics's conference presentation, 2024
Slide 1: BBO-10203, an orally bioavailable small molecule that disrupts the RAS:PI3Kα interaction
BBO-10203, an orally bioavailable small molecule that disrupts the RAS:PI3Kα interaction leading to pAKT and tumor growth inhibition in models of breast, lung and colorectal cancer Pedro J. Beltran, Ph.D. Chief Scientific Officer BBOT South San Francisco, CA
Slide 2: Conflict of Interests
Conflict of Interests Disclosures: Current employee and stockholder of BridgeBio Oncology Therapeutics (BBOT) 2 2
Slide 3: BBO-10203: a first-in-class Breaker of the RAS:PI3Kα interaction
BBO-10203: a first-in-class Breaker of the RAS:PI3Kα interaction F O O F N N N O • Binds specifically to the RBD of PI3Kα S N • Does not inhibit the kinase activity of PI3Kα • Forms covalent bond with C242 N N • Blocks binding of K-, H-, and N-RAS to PI3Kα Assay BBO-10203 • Agnostic to mutational st
Slide 4: Synchronized co-activation of MAPK and AKT pathways by RAS is important to maintain a productive malignant phenotype
Synchronized co-activation of MAPK and AKT pathways by RAS is important to maintain a productive malignant phenotype Normal GF RAS-driven GF GF MAPK Context RTK Malignant RTK RTK 120 Context 100 p110α p110α 80 A375 (BRAFV600E) % pERK 60 p85 p85 RAS 40 AKT 20 LU65 H358 RAF 0 AKT 0.01 0.1 1 10 100 100
Slide 5: Genetic disruption of the RAS:PI3Kα interaction inhibits KRAS G12D-driven tumor growth without hyperglycemia
Genetic disruption of the RAS:PI3Kα interaction inhibits KRASG12D – driven tumor growth without hyperglycemia Breaker MOA T208D and K227A mutations in the RAS-Binding Domain GF (RBD) of PI3Kα slow KRASG12D-driven growth Mutations RTK Disrupt RAS binding p110α p85 RAS AKT PRAS40 mTOR GSK3β S6K GF: Gr
Slide 6: Hypothesis: a small molecule that binds the RBD of PI3Kα could mimic the RBD mutations
Hypothesis: a small molecule that binds the RBD domain of PI3Kα could mimic the effect of the RBD mutations RAS PI3Kα / Efficacy No effect on Glucose Metabolism 6 6
Slide 7: The pocket occupied by the RAS:PI3Kα glue inspired us to design a Breaker
The pocket occupied by the RAS:PI3Kα glue inspired us to use structural information to design a Breaker Model of KRAS-p110α complex KRAS-p110α complex with glue Model showing the steric clash between BBO- 10203 (breaker) and the Y40 residue of KRAS C2 C2 Helical Helical Clash SBDD Breaker RBD Kinase
Slide 8: BBO-10203 covalently and selectively binds to PI3Kα RBD
BBO-10203 covalently and selectively binds to PI3Kα RBD Crystal structure of PI3Kα-RBD covalently labeled Electrostatic surface representation showing the binding pocket in PI3Kα with BBO-10203 where BBO-10203 binds (left) and Apo-protein (right) Sequence alignment of RBD of all four PI3K isoforms s
Slide 9: BBO-10203 binds specifically to the alpha isoform of PI3K and breaks its interaction with K-, H- and N-RAS
BBO-10203 binds specifically to the alpha isoform of PI3K and breaks its interaction with K-, H- and N-RAS PI3Kα PI3Kβ PI3Kδ PI3Kγ and BBO-10203 and BBO-10203 and BBO-10203 and BBO-10203 KRAS + KRAS + NRAS + HRAS + PI3Kα (no compound) Breaker-tethered PI3Kα Breaker-tethered PI3Kα Breaker-tethered PI
Slide 10: Cell potency and selectivity
Cell potency and selectivity AKT/ERK Signaling Gene Regulation Global Cysteine Proteomics 120 BT-474 BBO-10203 300nM vs. % pAKT Inhibition 100 80 NCI-H358 Alpelisib 300nM 60 6 40 120 20 0 100 0.01 0.1 1 10 100 100010000 -log10 (p-value) 4 -log10(FDR) nM 80 PK3CA_242 BBO-10203 Alpelisib PK3CA_215 60
Slide 11: Differences in cellular pAKT inhibition are driven by RAS' ability to activate AKT
Differences in cellular pAKT inhibition are driven by RAS’ ability to activate AKT Target Engagement pAKT 120 120 AMP 100 BT474 (HER2 ) 100 BT-474 (HER2AMP) G12D GP2d (KRAS ) % Free p110α 80 KYSE-410 (HER2AMP) 80 U87-MG (PTENnull) % pAKT GP2d (KRASG12D) 60 60 U87-MG (PTENnull) 40 40 20 20 0 0 0.01 0
Slide 12: Preclinical PK properties – good oral exposure
BBO-10203 preclinical PK properties – good oral exposure BBO-10203 CD-1 mouse PK BBO-10203 Dog PK IV 0.5 mg/kg 100000 10000 PO 10 mg/kg Plasma concentration (ng/mL) IV 3 mg/kg Plasma concentration (ng/mL) 10000 PO 30 mg/kg PO 30 mg/kg PO 100 mg/kg 1000 PO 100 mg/kg 1000 PO 300 mg/kg PO 600 mg/kg 100
Slide 13: BBO-10203 drives strong target engagement and efficacy in the KYSE-410 CDX model
BBO-10203 drives strong target engagement and efficacy in the KYSE-410 (HER2amp/KRASG12C) CDX model KYSE-410 PD Assay (8 hrs) KYSE-410 Efficacy 120 10 1600 (normalized to vehicle) ED50 (mg/kg) ED90 (mg/kg) Tumor volume (mm3) [BBO-10203] (μM) 100 1 [95% CI] [95% CI] 80 * 1200 2.5 3.9 % pAKT 60 * 0.1
Slide 14: BBO-10203 does not cause hyperglycemia and is well tolerated after 8-day repeated dosing
BBO-10203 does not cause hyperglycemia and is well tolerated after 28-day repeated dosing Body Weight % Change oGTT Results: Blood Glucose Levels Body Weight Change (%) 20 400 **** **** Vehicle (QDx1) Blood Glucose (mg/dL) **** **** **** Alpelisib (50 mg/kg, QDx1) 10 300 *** ** ** Alpelisib (20 mg/k
Slide 15: BBO-10203 inhibits pAKT leading to monotherapy and combination benefit with trastuzumab in HER2+ BC models
BBO-10203 inhibits pAKT leading to monotherapy and combination benefit with trastuzumab in the HER2+ BC models HER2amp Cell Lines BT-474 (HER2amp / PIK3CAK111N) MDA-MB-453 (HER2++ / PIK3CAH1047R) 120 1200 800 Tumor volume (mm3) 100 Tumor volume (mm3) 1000 80 600 800 % pAKT 60 600 400 40 400 200 200
Slide 16: BBO-10203 inhibits pAKT leading to monotherapy and combination benefit with KRASi in KRAS mutant tumors
BBO-10203 inhibits pAKT leading to monotherapy and combination benefit with KRASi in KRAS mutant tumors KRAS mutant cell Lines H358 (KRASG12C)) T84 (KRASG13D, PIK3CAE542K)) 1500 120 1000 Tumor volume (mm3) Tumor volume (mm3) 100 800 1000 80 600 % pAKT 60 400 500 40 200 ** ** * * 0 20 0 0 7 14 21 28
Slide 17: Strong G1 arrest and apoptosis in KRAS mutant NSCLC and PDAC models in combination with KRASi
Strong G1 arrest and apoptosis in KRAS mutant NSCLC and PDAC models in combination with KRASi H2122 CDX (KRASG12C, KEAP1mut, STK11mut) Apoptosis Cleaved Caspase-3 Positive Area / Proliferation Solid Tumor Area (μm2/ μm2) 0.12 Solid Tumor Area (μm2/ μm2) 0.04 *** 1400 Tumor volume (mm3) BrdU Positive
Slide 18: BBO-10203: a first-in-class Breaker of the RAS:PI3Kα interaction
BBO-10203: a first-in-class Breaker of the RAS:PI3Kα interaction • BBO-10203 provides a novel approach to inhibit the 2nd most mutated oncogene in human cancer • Potential monotherapy and combination benefit in HER2amp, KRAS and PI3Kα mutant tumors • BBO-10203 is agnostic to mutation status of eithe
Slide 19: The Team
The Team Olga Botvinnik Jin Ju Hiywot Takkele Frank McCormick Erik Larsen Felice Lightstone Howard Chang Sunyoung Lee Kalyan Vasudevan Dwight Nissley Tao Liao Yue Yang Michael Corbett Ken Lin Daniel Watson Dhirendra Simanshu Todd Harley Tony Chen Mike Monteith Bin Wang Patrick Alexander Anna Maciag