Development of Novel Therapeutic Molecules for Treatment of Squamous Head and Neck Cancers

机械疗法旨在设计，发现和开发选择性地 抑制多种致癌途径。在Mekanistic的产品组合中， EGFR和PI 3激酶，其被合理地设计为仅靶向这两个关键癌基因。的 PI 3激酶（PI 3 K）/AKT/mTOR通路在驱动肿瘤细胞存活和进展中起核心作用。 尽管制药工业进行了大量的努力，但PI 3 K抑制剂，包括选择性作为 以及pan-PI 3 K抑制剂在很大程度上不能产生针对实体瘤的单一药剂活性。EGFR是 是导致PI 3 K抑制剂抗性的适应性信号传导机制的主要贡献者。鳞状细胞 癌症是一个高度未满足医疗需求的领域， EGFR和PI 3 K的改变。该项目的中心目标是提供临床前概念验证， 支持开发一种理想地适合治疗鳞状上皮细胞癌头部的主要EGFR/PI 3 K抑制剂的单一疗法 和颈部癌症。我们在多个头颈鳞癌模型中生成的初步数据 强烈支持这一调查方向。第一阶段的目标是集中在评价前铅分子 MTX-531对患者来源的头颈癌异种移植物的抗肿瘤活性与MTX-531对患者来源的头颈癌异种移植物的抗肿瘤活性平行。 在大鼠和狗中进行药代动力学分析以评估生物利用度。

Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Among Mekanistic’s portfolio are dual and highly selective inhibitors of EGFR and PI3 kinase, which were rationally designed to only target these two critical oncogenes. The PI3 kinase (PI3K)/AKT/mTOR pathway plays a central role in driving tumor cell survival and progression. Despite intensive efforts of the pharmaceutical industry, PI3K inhibitors, encompassing isoform selective as well as pan-PI3K inhibitors, have largely failed to produce single agent activity against solid tumors. EGFR is a major contributor to the adaptive signaling mechanisms that lead to PI3K inhibitor resistance. Squamous cell carcinomas, which comprise an area of high unmet medical need, exhibit a high incidence of genomic alterations in both EGFR and PI3K. A central goal of this project is to provide preclinical proof of concept to support monotherapy development of a lead EGFR/PI3K inhibitor that is ideally suited to treat squamous head and neck cancers. Our preliminary data generated in multiple head and neck squamous cancer models strongly support this line of investigation. Phase I aims are focused on evaluation of the pre-lead molecule MTX-531 for its antitumor activity against patient-derived head and neck cancer xenografts in parallel with pharmacokinetic profiling in rats and dogs to assess bioavailability.