Selective RET Kinase and Its Mutant Inhibitors for the Treatment of Medullary Thyroid Cancer

 描述（由申请人提供）：癌症是美国的第二大死亡原因，迫切需要新的治疗方法来对抗这种疾病。1985年，RET基因被鉴定为一种通过染色体重排激活的新癌基因。从那时起，RET已被确定为几种癌症的驱动癌基因，特别是甲状腺髓样癌（MTC）。由于识别选择性RET抑制剂的挑战，MTC的治疗仍然是未满足的医疗需求。在开发RET激酶抑制剂的努力中，已经开发了皮摩尔的RET/VEGFR 2临床候选物，目前正在进行临床前研究。然而，VEGFR 2的抑制与血管靶向剂量限制性毒性相关，包括大多数VEGFR 2抑制剂药物患者的高血压。我们希望通过去除VEGFR 2活性并提高激酶组中的总体选择性来进一步开发抑制剂，从而实现患者中RET信号传导途径的最大/或完全抑制。我们将利用经验证的RET和VEGFR 2的计算模型、基于片段的筛选和潜在的X射线晶体结构信息来开发RET选择性超过VEGFR 2 30倍的临床候选药物。由此产生的选择性RET抑制剂可以最大限度地阻断RET信号通路，并将MTC的生存期从数月增加到数年。

 DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in United States and new therapeutics are desperately needed to combat the disease. In 1985, the RET (RE-arranged during Transfection) gene was identified as a novel oncogene activated through chromosomal rearrangement. Since then, RET has been identified as a driving oncogene in several cancers, especially for medullary thyroid cancer (MTC). Due to the challenges of identifying a selective RET inhibitor, a treatment for MTC is still an unmet medical need. In an effort to develop a RET kinase inhibitor, a picomolar RET/VEGFR2 clinical candidate has been developed and is currently in preclinical studies. However, the inhibition of VEGFR2 is associated with vascular on-target dose-limiting toxicities, including hypertension in patients for most VEGFR2 inhibitor drugs. We wish to further develop an inhibitor by removing VEGFR2 activity and improving overall selectivity in the kinome, thereby achieving maximal/or complete inhibition of the RET-signaling pathway in patients. We will utilize validated computational models of RET and VEGFR2, fragment-based screening, and potential X-ray crystal structural information to develop a clinical candidate with >30 times RET selectivity over VEGFR2. The resulting selective RET inhibitor could maximally block the RET signaling pathway and will increase MTC survival from months to multiple years.