Slide 1: Selectivity Matters and Pan-Mutant Allosteric Inhibition Delivers
Selectivity Matters and Pan-Mutant Allosteric Inhibition Delivers July 15, 2026 1
Slide 2: Legends: Forward-Looking Statements
Legends Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation are forward-looking statements. Such forward-looking statements include,
Slide 3: Agenda
Agenda Topic Presenter Welcome & Introduction Nicholas Saccomano, Ph.D. President & Chief Executive Officer of OnKure OnKure: A Differentiated Portfolio Benjamin Cravatt, Ph.D. Targeting Cryptic Allosteric Pockets Prof. of Chemistry and Norton B. Gilula Chair of Chemical Biology, Scripps Research Th
Slide 4: Today’s Guest KOLs
Today’s Guest KOLs Benjamin F. Cravatt, Ph.D. Professor of Chemistry and the Norton B. Gilula Chair of Chemical Biology at Scripps Research. A pioneer in chemical biology and proteomics, he has developed transformative technologies for protein and drug discovery and co-founded several biotechnology
Slide 5: OnKure is Developing a Differentiated Portfolio
OnKure is Developing a Differentiated Portfolio OnKure Therapeutics Portfolio • Developing PI3Kα PAN-mutant Two Lead PI3KαPAN Programs Inhibitors with the highest known • OKI-355 in Vascular Anomalies selectivity across helical and kinase • OKI-345 in Cancer mutations PI3Kα PAN-mut-selective inhib
Slide 6: PI3Kα Pathway is Pleiotropic: Central to Normal & Disease Signaling
PI3Kα Pathway is Pleiotropic: Central to Normal & Disease Signaling Disrupted cellular homeostasis due to mutant PI3Kα drives cancers & vascular anomalies OKI-355 OKI-345 Vascular Anomalies Oncology 6
Slide 7: A Differentiated Portfolio
A Differentiated Portfolio Next Program Program Initial Indication Discovery Preclinical Clinical Anticipated Status Milestone OKI-355 Vascular IND-Enabling IND PI3KαPAN Anomalies Studies Ongoing (1H 2027) mutant-selective inhibitor OKI-345 Breast IND-Enabling IND PI3KαPAN Cancer Studies Ongoing (1H
Slide 8: Candidate Profile for Potential BIC PI3Kα Pan-Inhibitors
Candidate Profile for Potential BIC PI3Kα Pan-Inhibitors Discovering pan-mutant inhibitors vs. the current landscape Selectivity Efficacy Safety Coverage Comparison of cellular selectivity of OnKure vs. competitor pan-mutant At least 10X Potential Best- Broad mutant PI3Kα inhibitors in-class anti- B
Slide 9: Benjamin Cravatt, Ph.D.
THERAPEUTICS Benjamin Cravatt, Ph.D.
Slide 10: Characteristics of High-Value Allosteric Pockets
Characteristics of High-Value Allosteric Pockets Not all allosteric pockets are equally druggable—successful targets share common features Desirable Properties Desirable Outcomes Rare Cryptic State Accessible Cryptic State Stabilization Pocket naturally samples an open conformation, enabling ligand
Slide 11: Cryptic Allosteric Pockets: A New Path to Better Drugs
Cryptic Allosteric Pockets: A New Path to Better Drugs Differentiated biology translates into differentiated therapeutics Traditional Active Site Cryptic Allosteric Pocket Key Value Drivers Conserved across Access previously paralogs (i.e., 500+ Often target-specific "undruggable" targets kinases)
Slide 12: Cryptic Allostery: A New Path to Better Drugs for PI3K
Cryptic Allostery: A New Path to Better Drugs for PI3K Differentiated biology translates into differentiated therapeutics Traditional Active Site Cryptic Allosteric Pocket Alpelisib: Orthosteric Inhibitor OKI: Allosteric Inhibitor • Highly conserved binding site • Often target-specific pocket • Comp
Slide 13: Allosteric Inhibition Proven in Ph+ CML
Allosteric Inhibition Proven in Ph+ CML SCEMBLIX® (asciminib) establishes clinical validation Mechanistic Rationale Clinical Validation ‐ First-in-class inhibitor targeting the ‐ Targets a site other than the ATP ABL myristoyl pocket binding pocket ‐ Designed to overcome resistance to ‐ Enables high
Slide 14: Sequential Innovation Creates Durable Competitive Advantage
Sequential Innovation Creates Durable Competitive Advantage Best-in-class franchises emerge from iterative gains in potency, selectivity, resistance coverage, & safety 1st Gen 2nd Gen 3rd Gen 4th Gen Franchise Higher Potency, Enhanced First-in-Class Mutant Target Coverage Improved Therapeutic Index
Slide 15: Robert T. Abraham, Ph.D.
Robert T. Abraham, Ph.D.
Slide 16: PI3Kα Pathway is Pleiotropic: Central to Normal & Disease Signaling
PI3Kα Pathway is Pleiotropic: Central to Normal & Disease Signaling Disrupted cellular homeostasis due to mutant PI3Kα drives cancers & vascular anomalies OKI-355 OKI-345 Vascular Anomalies Oncology 16
Slide 17: PI3Kα: From Target Discovery toward Mutant-Selective Medicines
PI3Kα: From Target Discovery toward Mutant-Selective Medicines PI3Kα mutations occur in major subset of vascular anomalies and ~15% of all cancers 1983–2000 Next Generation Target Discovery The Emerging Opportunity • Studies of a viral oncogene identify • Pan-mutant PI3Kα inhibitors PI3Kα as a drive
Slide 18: Challenges in Drugging PI3Kα
Challenges in Drugging PI3Kα Next-generation mutant-selective inhibitors aim to preserve efficacy while reducing wild-type inhibition & metabolic toxicity Chemistry Challenges The Path Forward • Development of a pan-mutant inhibitor that targets • Mutant-selective inhibition the ATP binding site (or
Slide 19: OnKure’s Programs
§OnKure THERAPEUTICS OnkKure’s Programs
Slide 20: Therapeutic Selectivity & Clinical Performance
Therapeutic Selectivity & Clinical Performance Superior selectivity has translated into improved clinical outcomes Ideal Performance OnKure’s Program Goals − Improved target coverage ‐ Minimize wild-type PI3Kα inhibition − Better safety − Greater combination ‐ Maximize PI3Kα mutant potential inhibit
Slide 21: OnKure’s Structure-Based Drug Design Platform Enables Discovery of Allosteric PI3Kα Pan-Mutant Inhibitors
OnKure’s Structure-Based Drug Design Platform Enables Discovery of Allosteric PI3Kα Pan-Mutant Inhibitors Allosteric pan-inhibitor design ATP Site • Targeting regions proximal to PI3Kα H1047 Allosteric mutations: Mutant Site − H1047 allosteric mutant site (lead) − OnKure-discovered E-mutant site (pr
Slide 22: Candidate Profile for Potential BIC PI3Kα Pan-Inhibitors
Candidate Profile for Potential BIC PI3Kα Pan-Inhibitors Discovering pan-mutant inhibitors vs. the current landscape Selectivity Efficacy Safety Coverage Comparison of cellular selectivity of OnKure vs. competitor pan-mutant At least 10X Potential Best- Broad mutant PI3Kα inhibitors in-class anti- B
Slide 23: Selectivity Provides Deeper Responses when Dosed to MTD
Selectivity Provides Deeper Responses when Dosed to MTD A wider therapeutic window allows for greater mutant target coverage OKI-345 Drives Regressions in MCF7 Cellular Selectivity vs. SK-BR-3 WT Helical (E545K) Domain Mutant Xenograft Model PI3Kα Mutation OKI-345 MCF7 TGI selectivity 700 compound H
Slide 24: OnKure’s Thesis: Best-in-Class Selectivity Enables Greater Target Coverage
OnKure’s Thesis: Best-in-Class Selectivity Enables Greater Target Coverage to Unlock an Expanded Therapeutic Index inavolisib & alpelisib RLY-2608 STX-478 OKI-345 1x selectivity 2x selectivity 3x selectivity 18x selectivity Greater separation between the red & blue lines reflects an expanded therape
Slide 25: OnKure is Developing a Differentiated Portfolio
OnKure is Developing a Differentiated Portfolio OnKure Therapeutics Portfolio • Developing PI3Kα PAN-mutant Two Lead PI3KαPAN Programs Inhibitors with the highest known • OKI-355 in Vascular Anomalies selectivity across helical and kinase • OKI-345 in Cancer mutations PI3Kα PAN-mut-selective inhib
Slide 26: Q&A
4OnKure THERAPEUTICS Q&A
Slide 27: Selectivity Matters and Pan-Mutant Allosteric Inhibition
Selectivity Matters and Pan-Mutant Allosteric Inhibition Delivers July 15, 2026