On December 10, 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 for the first time preclinical data on ETX-197/BG-68501, a potential best-in-class oral, selective CDK2 inhibitor at the 47th Annual San Antonio Breast Cancer Symposium ("SABCS") in San Antonio, Texas (Press release, ENSEM Therapeutics, DEC 10, 2024, View Source [SID1234649017]). ETX-197/BG-68501 has a differentiated preclinical profile and the potential to deliver clinical benefit to patients with tumors associated with CDK2 dependency.

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CDK2 is a well-established vulnerability of multiple cancers, including tumors with increased expression of Cyclin E (CCNE) or the mutation/loss of the Retinoblastoma 1 gene (RB1). There are currently no approved CDK2 specific drugs. ETX-197/BG-68501 was designed through ENSEM’s Kinetic Ensemble platform to induce previously unexplored interactions within the CDK2 ATP binding pocket, leading to increased potency and selectivity compared to other CDK2 inhibitors.

ETX-197/BG-68501 shows tight binding (slow off-rate) for CDK2 which results in potent and concordant pharmacodynamic modulation and anti-proliferative activity both in vitro and in vivo. ETX-197/BG-68501 is 100-fold more selective for CDK2 over other kinases in the CDK family and this superior selectivity extends more broadly against 385 other kinases, indicating the potential for promising tolerability in the clinic.

In mouse xenograft studies using a CCNE-amplified ovarian cancer cell line or patient-derived tumors, ETX-197/BG-68501 showed sustained target engagement, dose-dependent tumor growth inhibition with excellent tolerability. ETX-197/BG-68501 demonstrated single agent efficacy in a breast cancer xenograft model that had acquired resistance to a CDK4/CDK6 inhibitor. In addition, ETX-197/BG-68501 showed anti-tumor activity in other in vitro and in vivo tumor models including small cell lung and ovarian cancers, indicating its broad clinical potential beyond breast cancer.

"Inhibiting CDK2 potently and selectively over other CDK family members represents a significant challenge," said Shengfang Jin, CEO and Co-Founder of ENSEM. "The promising preclinical results with ETX-197/BG-68501 underscore the potential of our Kinetic Ensemble platform to discover small molecules against high value and difficult to drug targets." She noted that BeiGene is currently conducting a first-in-human Phase 1a/1b clinical study (NCT06257264) to assess the safety tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ETX-197/BG-68501, and is presenting a "Trial-in-Progress" poster for this ETX-197/BG-68501 clinical study at the Symposium.

Poster Details

Title: ETX-197/BG-68501, a potential best-in-class potent, selective oral small molecule CDK2 inhibitor, has anti-tumor activity in cancer models with Cyclin E amplification or deficiency in the Retinoblastoma 1 gene
Poster ID: P4-12-29
Sessions: Poster Session
Date/Time: Thursday, December 12, 2024, from 5:30 to 7 p.m. CT
Location: Halls 2-3