P1, N=464, Recruiting, Debiopharm International SA | Trial completion date: Dec 2026 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Dec 2027

We evaluated lunresertib (RP-6306), a selective first-in-class PKMYT1 inhibitor, in CCNE1 -amplified and wild-type GEA cell lines to define its effects on cell viability, DNA damage, and gene expression changes...In a syngeneic murine model of CCNE1 -amplified gastric cancer, we further identified that PKMYT1 inhibition induced T cell infiltration and tumor microenvironment remodeling, and synergized with anti-PD-1 therapy to drive tumor regression. Together, these results support further development of PKMYT1 inhibition in combination with PD-1 blockade for CCNE1 -amplified GEA.

P1, N=6, Active, not recruiting, University Health Network, Toronto | N=24 --> 6 | Trial completion date: Dec 2026 --> Jan 2026 | Trial primary completion date: Dec 2026 --> Oct 2025

Molecular dynamics simulations, Hirshfeld surface analysis, dynamic cross-correlation matrix (DCCM), and MM/GBSA calculations elucidated the molecular mechanism underlying MY-14's interaction with PKMYT1. MY-14 emerged as a promising compound for the development of a novel PKMYT1 inhibitor.

Further investigations revealed that compound A30 exerted a highly synergistic effect with gemcitabine in CCNE1-amplified cancer models...Pharmacokinetic profiling indicated that compound A30 exhibits liver microsomal stability, favorable plasma stability, minimal CYPs inhibition, and acceptable overall pharmacokinetic properties. Together, these findings establish that compound A30 represents a promising lead for the further development of selective PKMYT1 inhibitors.

By integrating CRISPR-Cas9 with functional assays and transcriptomics, our study established a framework for decoding resistance mechanisms and highlights potential therapeutic strategies to enhance RX-3117 efficacy in NSCLC. We demonstrated for the first time that aberrant DNA repair and cell cycle dysregulation led resistance, identifying PKMYT1 as a promising target.

P2, N=28, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=78 --> 28

P1, N=9, Terminated, Exelixis | N=124 --> 9 | Trial completion date: Nov 2027 --> May 2025 | Recruiting --> Terminated | Trial primary completion date: Nov 2027 --> May 2025; Company Decision

P1, N=38, Terminated, Repare Therapeutics | Trial completion date: Nov 2026 --> Feb 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2026 --> Feb 2025; Sponsor decided to terminate the study

P1, N=67, Terminated, Repare Therapeutics | N=104 --> 67 | Trial completion date: Apr 2025 --> Aug 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Aug 2024; Sponsor decided to terminate the study

Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

P2, N=78, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Dec 2024 --> Dec 2025