Targeting mutant KRAS for cancer therapy

描述（由申请人提供）：突变型KRAS（mut-KRAS）是原型不可治疗的癌症靶标。在许多癌症类型的25%的患者肿瘤中发现，估计在美国每年有320，000人被诊断患有mut-KRAS，其中大多数人将死于他们的疾病。KRAS是30多年来研究最多的人类致癌基因，但没有有效的治疗方法。Mut-KRAS在驱动肿瘤生长和对治疗的抗性方面起着关键作用，其作用如此强大，以至于它超越了 许多新的分子靶向信号药物正在开发的癌症今天，使他们不能用于患者与mut-KRAS。因此，寻找抑制mut-KRAS的新药物可以说是当今癌症中最重要的未满足的医疗需求。我们已经将CNKSR 1确定为替代靶标，其抑制将阻断mut-KRAS癌细胞的生长而不影响野生型-KRAS（wt-KRAS）细胞生长。CNKSR 1是一种与KRAS相关的蛋白质，在调节癌细胞生长和侵袭的膜信号纳米簇中。CNKSR 1具有与膜磷脂酰肌醇结合的普列克底物蛋白同源（PH）结构域，并且我们已经表明该PH结构域对于mut-KRAS活性是至关重要的。使用CNKSR 1的PH结构域的同源模型、分子对接和药物设计，然后通过合成化学，我们已经鉴定了以高亲和力结合CNKSR 1的PH结构域、抑制KRAS信号传导、抑制癌细胞生长并具有体内抗肿瘤活性的化合物。因此，我们的假设是：“虽然目前对mut-KRAS肿瘤没有有效的治疗方法，但靶向CNKSR 1的PH结构域（一种对mut-KRAS细胞生长必需而非wt-KRAS细胞生长必需的蛋白）为开发小分子抑制剂作为治疗mut-KRAS肿瘤的药物提供了机会。”我们的研究目的是：1）合成并体外评价具有药物样性质的CNKSR 1 PH结构域抑制剂小分子;和2）研究药代动力学和抗肿瘤活性，为后期临床前开发提供候选药物。

DESCRIPTION (provided by applicant): Mutant KRAS (mut-KRAS) is the prototypical undruggable cancer target. It is found in 25% of patient tumors across many cancer types and an estimated 320,000 individuals/yr who will be diagnosed with mut-KRAS in the US most of who will die of their disease. KRAS has been the single most studied human oncogene for over 30 years and yet there is no effective treatment. Mut-KRAS plays a critical role in driving tumor growth and resistance to therapy, and its effects are so powerful that it overrides the activity of many of the new molecularly targeted signaling drugs being developed for cancer today such that they cannot be used in patients with mut-KRAS. Thus, finding new agents that inhibit mut-KRAS is arguably the most important unmet medical need in cancer today. We have identified CNKSR1 as a surrogate target whose inhibition will block the growth of mut-KRAS cancer cells without affecting wild type-KRAS (wt-KRAS) cell growth. CNKSR1 is a protein associated with KRAS in the membrane signaling nanocluster that regulates cancer cell growth and invasion. CNKSR1 has a pleckstrin homology (PH) domain that binds to membrane phosphatidylinositols and we have shown this PH-domain is critical for mut-KRAS activity. Using a homology model for the PH-domain of CNKSR1, molecular docking and drug design, followed by synthetic chemistry we have identified compounds that bind with high affinity to the PH domain of CNKSR1, inhibit KRAS signaling inhibit cancer cell growth and have in vivo antitumor activity.. Thus, our hypothesis is: "While there is currently no effective therapy for mut-KRAS tumors, targeting the PH-domain of CNKSR1 a protein necessary for mut-KRAS but not wt-KRAS cell growth, offers a window of opportunity for developing small molecules inhibitors as agents to treat mut-KRAS tumors" The objectives of our study are: 1) to synthesize and evaluate in vitro the small molecules as CNKSR1 PH-domain inhibitors with drug-like properties; and 2) to investigate the pharmacokinetics and antitumor activity to provide a drug candidate for late pre-clinical development.