On December 1, 2024 Ensem Therapeutics, Inc. (ENSEM), a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble platform to advance innovative small molecule precision medicines for oncology, reported the first presentation of preclinical data on ETX-636, a potential best-in-class novel allosteric pan-mutant-selective PI3Kα inhibitor and degrader (Press release, ENSEM Therapeutics, DEC 10, 2024, View Source [SID1234649019]). ETX-636 has a differentiated preclinical profile and the potential to deliver clinical benefit to patients with tumors harboring all forms of mutant PI3Kα. The ETX-636 preclinical data is being presented in a poster session during the 47th Annual San Antonio Breast Cancer Symposium ("SABCS") in San Antonio, Texas, on Dec. 12.
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PI3Kα is among the most frequently mutated oncogenes, with activating mutations seen in approximately 16 percent of all tumors and up to 40 percent of hormone receptor positive/HER2-negative advanced breast cancer. However, wildtype PI3Kα is also central to glucose homeostasis and ATP-binding-site orthosteric inhibitors target both mutant and wildtype PI3Kα, resulting in hyperglycemia which limits the clinical utility of these therapeutics.
ETX-636 is a novel orally bioavailable allosteric pan-mutant-selective PI3Kα inhibitor and degrader. This dual mechanism of action results in deep and durable pathway inhibition and induces concordant tumor regression in kinase and helical domain PI3Kα-mutant breast cancer xenografts without inducing wildtype PI3Kα inhibition-mediated hyperglycemia or other toxicities. Additionally, in an ER-positive, HER2-negative, PI3Kα-mutant breast cancer xenograft, ETX-636 is efficacious as a single agent and shows synergistic activity with the standard-of-care agent fulvestrant. ENSEM believes this molecule will significantly improve outcomes for patients with PI3Kα mutations, whether in cancer or rare diseases.
"The promising preclinical results with ETX-636 underscore the potential of our Kinetic Ensemble platform to discover small molecules against high value and difficult to drug targets," said Shengfang Jin, CEO and Co-Founder of ENSEM. "Targeting mutant PI3Kα within tumors while sparing wildtype PI3Kα in normal tissues represents a significant clinical challenge. ETX-636 is a potent mutant-specific allosteric PI3Kα inhibitor and degrader which differentiates it from other compounds in its class." She noted that ETX-636 is completing IND-enabling studies with a first-in-human clinical trial anticipated in the first half of 2025. ENSEM will evaluate ETX-636 as a monotherapy and in combinations with standard-of-care agents in cancer patients harboring PI3Kα mutations.
Poster Details
Title: ETX-636, a Potential Best-In-Class, Oral Small Molecule Allosteric Pan-Mutant-Selective PI3Kα Inhibitor and Degrader
Poster ID: P4-12-18
Sessions: Poster Session 4
Date/Time: Thursday, December 12, 2024, from 5:30 to 7 p.m. CT
Location: Halls 2-3