Targeting mutant KRAS for cancer therapy

描述(由申请人提供)：突变的KRAS(mut-KRAS)是典型的不可药物治疗的癌症靶点。在许多癌症类型的25%的患者肿瘤中发现了它，在美国估计每年将有32万人被诊断为MUT-KRAS，其中大多数人将死于他们的疾病。30多年来，KRAS一直是研究最多的单一人类癌基因，但目前还没有有效的治疗方法。MUT-KRAS在推动肿瘤生长和抵抗治疗方面起着关键作用，其作用是如此强大，以至于超过了 许多新的分子靶向信号药物目前正在为癌症开发，因此它们不能用于MUT-KRAS患者。因此，寻找抑制MUT-KRAS的新药物可以说是当今癌症最重要的未得到满足的医学需求。我们已经确定CNKSR1是一个替代靶点，它的抑制将阻止MUT-KRAS癌细胞的生长，而不会影响野生型KRAS(wt-KRAS)细胞的生长。CNKSR1是一种与KRAS相关的蛋白质，位于膜信号纳米簇中，调节癌细胞的生长和侵袭。CNKSR1有一个与膜磷脂酰肌醇结合的Pleckstrin同源(PH)结构域，我们已经证明这个PH结构域对MUT-KRAS活性至关重要。利用CNKSR1的PH结构域的同源模型、分子对接和药物设计，再加上合成化学，我们已经鉴定出与CNKSR1的PH结构域具有高亲和力、抑制KRAS信号转导、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：虽然目前还没有有效的治疗MUT-KRAS肿瘤的方法，但靶向CNKSR1的PH域是MUT-KRAS细胞生长所必需的蛋白质，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之窗。我们研究的目的是：1)合成并在体外评估具有药物样特性的CNKSR1 PH域抑制剂的小分子；2)研究CNKSR1的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.