On July 11, 2024 MEKanistic Therapeutics Inc., a biotechnology company pioneering the development of next-generation kinase inhibitors for cancer treatment, reported the peer-reviewed publication of new preclinical research on its lead candidate, MTX-531, an investigational dual-targeting therapy, in Nature Cancer (Press release, Mekanistic Therapeutics, JUL 11, 2024, View Source [SID1234644798]). MTX-531 is a potential first-in-class therapy uniquely designed to inhibit both EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase), two critical proteins involved in cancer cell survival and proliferation.

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"We are excited to share the positive MTX-531 preclinical research published in Nature Cancer, which we believe show promising signals toward a novel solution to addressing the root cause of resistance to current cancer treatments," said Danny Cunagin, chief executive officer, MEKanistic Therapeutics. "By targeting critical adaptive resistance mechanisms with a dual inhibition strategy, we aim to significantly halt cancer progression compared to single-target treatments, and look forward to advancing this innovative therapy to patients in clinical trials."

Key Findings of MTX-531 Study

High Potency, Selectivity Leading to First of Its Kind Tolerability

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. In addition, MTX-531 did not cause hyperglycemia in mice at therapeutic doses, unlike other known pan-PI3K inhibitors, which have been reported to significantly increase blood glucose and insulin levels both in preclinical and clinical settings.

Judith Sebolt-Leopold, PhD, chief scientific officer, MEKanistic Therapeutics, commented, "MTX-531 is the first PI3K inhibitor capable of selectively co-targeting EGFR and the first known pan-PI3K inhibitor that does not induce hyperglycemia, a known challenge with PI3K inhibitors that often leads to treatment discontinuation. This unique feature, achieved through precise targeting enabled by MTX-531’s computational design, confers a favorable therapeutic index and resilience to adaptive resistance mechanisms not observed in prior PI3K inhibitor clinical programs."

Robust Tumor Suppression as Monotherapy and in Combination Therapy

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. Complete tumor regressions were observed across a broad dose range, with survival improvement ranging from 62% to >500% across models.

In addition, when combined with a MEK inhibitor (trametinib) or a KRAS inhibitor (sotorasib), treatment with MTX-531 more than doubled the incidence of tumor regressions achieving a 100% objective response rate in multiple KRAS mutant colorectal (CRC) and pancreatic tumor models.

Dr. Sebolt-Leopold added, "Our collective preclinical data show that MTX-531 effectively inhibits tumor growth in cancers with PIK3CA and KRAS mutations, which often lead to aggressive behavior and resistance to standard therapies. MTX-531 was well tolerated and outperformed the combination of drugs that individually target EGFR and PI3K. These findings highlight the versatility and broader potential of MTX-531 in treating hard-to-treat cancers."

The scientific paper can be accessed at the following link: View Source

About MTX-531 Development

Investigational new drug-enabling toxicology studies sponsored by the National Cancer Institute’s Experimental Therapeutics (NExT) Program are currently underway. The NExT Program aims to advance clinical practice by supporting promising new drug discovery and development projects. Through this program, MEKanistic Therapeutics collaborates with NCI staff and contractors on a milestone-driven project team to conduct these studies and assess MTX-531’s safety and efficacy in patients with cancer.

"Our partnership with the NCI is a testament to the promising potential of MTX-531," said Christopher Whitehead, PhD, co-founder and chief operating officer, MEKanistic Therapeutics. "With their support and our focused efforts on GMP manufacturing and drug product development, we are poised to make significant strides in bringing this innovative therapy closer to clinical trials and ultimately to patients in need."