MTX-531 / Mekanistic Therap - LARVOL DELTA

A precision polypharmacology approach to co-target EGFR and PI3 kinase: the power of structure-based drug design to generate therapeutic agents with versatility in multiple combination settings (AACR 2025) - "In vivo studies were carried out in KRAS G12D mutant tumor-bearing mice showing that treatment with MTX-531 led to striking enhancement of KRAS inhibitor (MRTX-1133) activity against a broad spectrum of gastrointestinal cancers (pancreatic, colorectal, gastric) as evidenced by a high incidence of durable tumor regressions. Collectively, these studies demonstrate the versatility of MTX-531 to serve as the backbone of combination regimens across diverse modalities encompassing treatment with targeted therapies, radiation, or immune checkpoint inhibitors. Based on its promising preclinical profile, MTX-531 represents a first-in-class approach to precision polypharmacology that demonstrates the power of rational structure-based drug design to target multiple resistance drivers in a single molecule."

IO biomarker • Breast Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • EGFR • KRAS

MEKanistic Therapeutics Inc.'s First-in-Class Dual EGFR and PI3K Investigational Therapy, MTX-531, Demonstrates Significant Tolerability and Durable Tumor Regressions in Preclinical Cancer Models (PRNewswire) - "MEKanistic Therapeutics...announced the peer-reviewed publication of new preclinical research on its lead candidate, MTX-531, an investigational dual-targeting therapy, in Nature Cancer....Preclinical studies demonstrated that MTX-531 exhibits nanomolar potency against both EGFR and PI3K (14.7 nM for EGFR, 6.44 nM for PI3K), with a high degree of selectivity as determined by broad kinome testing....MTX-531 monotherapy led to significant tumor regression in preclinical models of head and neck squamous cell carcinoma (HNSCC). Oral therapy effectively inhibited PI3K and EGFR signaling in a balanced fashion, achieving objective responses in every HNSCC model evaluated."

Preclinical • Squamous Cell Carcinoma of Head and Neck

A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance. (PubMed, Nat Cancer) - "Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors."

Journal • Colorectal Cancer • Diabetes • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • EGFR • KRAS

MTX-531, a first-in-class pan-PI3K inhibitor spares hyperinsulinemia yielding durable tumor regressions and resilience to adaptive resistance (AACR 2024) - "The versatility of MTX-531 in both the single agent and combination settings offers a breadth of development strategies that continue to evolve as new combination candidates become available. MTX-531 is currently undergoing advanced preclinical development for anticipated first in human clinical trials in late 2024."

Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • EGFR • KRAS • PIK3CA • PPARG

MEKanistic Therapeutics First-in-Class Cancer Clinical Candidate Approved to Receive Continued Development Support through the National Cancer Institute's Experimental Therapeutics (NExT) Program (PRNewswire) - "MEKanistic Therapeutics...announced today that its investigational cancer clinical candidate MTX-531 has been approved for receiving continued development support from the National Cancer Institute's (NCI) Experimental Therapeutics (NExT) Program....Through the NExT Program, MEKanistic Therapeutics will work with NCI staff and their contractors as part of a milestone-driven project team towards conducting IND enabling studies and clinical trial support, assessing the drug's safety and efficacy in cancer patients."

Licensing / partnership • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor