OnKure Therapeutics (NASDAQ:OKUR) used a scientific webcast to outline its strategy for developing mutant-selective PI3Kα inhibitors, emphasizing allosteric inhibition as a potential way to improve efficacy and tolerability in cancer and vascular anomalies.
Nick Saccomano, president and chief executive officer of OnKure Therapeutics, said the company is advancing two lead candidates: OKI-355 for vascular anomalies and OKI-345 for breast cancer and other cancers. Saccomano said both molecules were designed for their respective indications and that the company continues to guide toward investigational new drug applications for both candidates in the first half of 2027.
Company Highlights Two Lead Candidates
Saccomano said PI3Kα plays important roles in normal biology, including survival, proliferation and glucose homeostasis. When mutated into an activated state, he said, the pathway can support abnormal cell proliferation in vascular anomalies and contribute to cancer cell proliferation, metastasis and resistance.
The company presented OKI-355 as a candidate for vascular anomalies and OKI-345 as a candidate for cancer. Saccomano said OnKure is also building discovery programs aimed at additional therapeutic opportunities in vascular anomalies.
According to Saccomano, selectivity is central to the company’s approach because wild-type PI3Kα is present in many cells and regulates important processes. He said inhibiting wild-type PI3Kα can lead to “significant and predictable side effects.” The company said it is evaluating factors including preclinical efficacy, safety, target coverage, combinability, mutation resistance and intellectual property as it advances its programs.
Experts Discuss Allosteric Inhibition
Ben Cravatt, professor and chair of chemical biology at The Scripps Research Institute, discussed the scientific rationale for targeting allosteric, or non-orthosteric, binding pockets. Cravatt said such pockets may be exposed through protein motions and can allow small molecules to regulate proteins in ways not possible through conventional active-site inhibition.
Cravatt said allosteric approaches may offer advantages in kinase drug discovery, including greater selectivity and the ability to avoid direct competition with ATP, which binds kinase active sites at high intracellular concentrations. He cited asciminib, an allosteric BCR-ABL inhibitor used in Philadelphia chromosome-related chronic myeloid leukemia, as an example of how allosteric kinase inhibition has translated into clinical utility.
For PI3Kα, Cravatt said first-in-class inhibitors such as alpelisib target the ATP binding pocket, which creates challenges around selectivity and wild-type inhibition. He said OnKure’s allosteric strategy is intended to exploit cryptic binding pockets that may be more accessible in mutant forms of PI3Kα than in the wild-type protein.
PI3Kα Pathway and Therapeutic Window
Robert Abraham, executive vice president and head of cancer biology at Odyssey Therapeutics, reviewed the biology of the PI3K pathway and its role in cancer and vascular anomalies. Abraham said mutations in the PI3K pathway have been observed in about 15% of cancers, while mutations in PI3Kα are also found in syndromes involving vascular anomalies.
Abraham noted that alpelisib was approved in 2019 for PIK3CA-mutant, ER-positive, HER2-negative breast cancer and later for CLOVES and other PI3Kα-related overgrowth syndromes. However, he said existing drugs are limited by therapeutic window and side effects, including hyperglycemia, skin rash and diarrhea.
“It all comes down to tolerability,” Abraham said, adding that chronic dosing requires an improved therapeutic window to avoid dose reductions and discontinuations. He said a mutant-selective molecule could allow deeper inhibition of mutant PI3Kα while sparing wild-type PI3Kα, potentially improving tolerability and supporting combination use.
Preclinical Data and Safety Focus
Saccomano presented one preclinical tumor growth inhibition example involving OKI-345 in an MCF7 model carrying an E545 mutation. He said OKI-345 showed greater activity at tested doses than STX-478 in that model, and described the result as a “unique property” of OnKure’s molecules. He said the company believes improved selectivity may translate into better target engagement and tolerability.
During the question-and-answer session, analysts asked about resistance mechanisms, vascular anomaly patient selection and safety monitoring. Saccomano said the company is studying resistance mechanisms internally and with academic collaborators, including how tumors may progress on standard-of-care or experimental drugs.
Sam Agresta, chief medical officer of OnKure Therapeutics, said the company expects to monitor insulin, glucose and C-peptide in clinical studies, given known hyperglycemia risks associated with PI3K inhibitors. He said the company will look for low rates of clinically meaningful hyperglycemia and will evaluate dose interruptions, reductions and discontinuations, with a goal of maintaining dose intensity and target inhibition.
In vascular anomalies, Saccomano said selectivity may be especially important because patients may remain on therapy for long periods and because some patients may be young. He said the company expects to sequence patients and analyze outcomes by mutation, rather than treating without genetic characterization.
Saccomano closed by reiterating the company’s goal of advancing OKI-345 into cancer and OKI-355 into vascular anomalies, saying OnKure believes the candidates have the potential to be best-in-class molecules as they move toward the clinic.
About OnKure Therapeutics (NASDAQ:OKUR)
OnKure Therapeutics, Inc (NASDAQ: OKUR) is a clinical-stage biopharmaceutical company focused on the development of novel therapies for oncology and autoimmune diseases. Headquartered in Westlake Village, California, OnKure is advancing small molecule drug candidates designed to modulate key signaling pathways implicated in cancer cell growth and immune system function.
The company’s lead oncology asset, OKI-179, is an orally available histone deacetylase (HDAC) inhibitor being evaluated in Phase I and Phase II clinical studies for a range of solid tumors.
