MTAP deletion

We analyze recent advances and ongoing investigations, as well as future directions in the development of epigenetic therapies in solid tumors. Overall, epigenetic inhibitors are poised to become an expanding pillar of precision oncology, bridging chromatin biology with clinical benefit.

P1, N=362, Not yet recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

Here, we investigated mechanisms of acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance...Instead, resistance was associated with collateral sensitivity to MEK inhibition and enrichment of MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as an actionable collateral vulnerability in MTAP-null NSCLC cells that acquire resistance to PRMT5 inhibition.

P2/3, N=470, Recruiting, Bristol-Myers Squibb

P1/2, N=342, Recruiting, Servier Bio-Innovation LLC | Active, not recruiting --> Recruiting | N=104 --> 342

P1/2, N=104, Active, not recruiting, Servier Bio-Innovation LLC | Recruiting --> Active, not recruiting

Herein, we report the design and optimization of a novel series of pyridazinone-based MAT2A inhibitors via a ring-opening strategy from AGI-41998...Mechanically, treatment with 33 markedly reduced SAM and sDMA levels both in vitro and in vivo. Collectively, these results establish pyridazinone as a privileged scaffold for MAT2A inhibition and identify compound 33 as a compelling lead for further preclinical development.

Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM.

P1/2, N=17, Not yet recruiting, Ankit Mangla, MD

P1/2, N=53, Completed, Amgen | Active, not recruiting --> Completed

Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.

P1, N=60, Recruiting, Memorial Sloan Kettering Cancer Center