Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors

PARP抑制剂(PARPI)对BRCA1/2肿瘤抑制基因缺失的肿瘤特别有效 BRCA活性肿瘤中活性有限的基因。有一种尚未得到满足的医疗需求，即开发有针对性的 将增强BRCA1/2野生型肿瘤的PARPI活性并增加化疗效率的治疗药物 这些恶性肿瘤的放射敏感性。BRCA1/2蛋白是同源基因的重要组成部分 重组(HR)双链DNA修复机制。PARPI的合成杀伤力来自于预防 癌细胞无法克服的HR DNA双链断裂(DSB)修复机制 致命的DNA损伤。PARPI对BRCA1/2缺陷或其他DNA修复的细胞具有选择性毒性 在一些三阴性乳腺癌中发现的通路突变。最近的一份报告表明，PI-3 抑制激酶(PI-3K)削弱BRCA1/2的表达并使BRCA熟练的癌症对PARP敏感 抑制力。因此，我们要在这个提议中检验的中心假设是，一个组合的双PI-3K 抑制剂(PI-3Ki)/PARP抑制剂将通过至少两种途径攻击癌细胞的DNA修复机制 正交通路和将PARPI临床活性扩展到BRCA1/2和/或其他缺陷之外 DNA修复缺陷。我们提案的一个创新部分是，我们在Silico开发了第一个 同时抑制PI-3K和PARP活性的小分子抑制性化学型(例如 SRX3128；初步结果)。我们已经证明了SRX3128：1)增强细胞的“概念证明” DNA损伤后死亡2)同时抑制同一肿瘤中的两个靶标DNA修复和PI-3K 细胞和3)在正常细胞中的毒性比同等条件下的个体抑制性化学类型要小 对目标的威力。我们建议的意义在于我们有能力提供一个可优化的 有望通过多种正交机制有效抑制DNA修复的单一抗癌药物 以及对DNA损伤剂具有化学辐射敏感性的肿瘤细胞。该提案将通过以下方式对此方法进行评估 实现以下目标为第二阶段的工作奠定了基础，以优化预期的双抑制剂主成分 化合物(S)到临床候选：目的(任务)#1.开发一种双重PI-3激酶/PARP抑制剂。目标(任务) #2.开发用于设计化合物的电子对接的预测性计算PARP模型。 方法：改进我们的PARP模型的电子PARP配体匹配参数，直到高PARP对接/PARP- 实现了测定-抑制相关。目标(任务)#3.确定双重PI-3K/PARP的治疗窗口 抑制力。方法：比较神经肿瘤干细胞和正常神经干细胞的毒性 (NSCs)暴露于单一PARP抑制剂或PI-3K抑制剂与双重PARP/PI-3K抑制条件下。 这项研究的意义在于，它将大大扩大PARP抑制的范围，使其适用于BRCA-Experent 癌症。这一创新的方法使用两种不同的经过验证的机制来治疗癌症， 挑战一药一靶教条的化合物。

PARP inhibitors (PARPi) are particularly efficacious in tumors deficient in the BRCA1/2 tumor suppressor genes but of limited activity in BRCA competent tumors. There is an unmet medical need to develop targeted therapeutic agents which will augment PARPi activity for BRCA1/2 wild type cancers and to increase chemo- radiosensitivity in these malignancies. BRCA1/2 proteins are essential components of the homologous recombination (HR) double-strand DNA repair mechanism. PARPi's synthetic lethality derives from preventing the HR DNA double-strand break (DSB) repair mechanism which the cancer cell cannot overcome resulting in lethal DNA damage. PARPi are selectively toxic to cells with BRCA1/2 deficiencies or other DNA repair pathway mutations as found in some triple negative breast cancers. A recent report demonstrated that PI-3 kinase (PI-3K) inhibition impairs BRCA1/2 expression and can sensitize BRCA-proficient cancers to PARP inhibition. Hence, our central hypothesis to be tested in this proposal is that a combination dual PI-3K inhibitors (PI-3Ki)/ PARP inhibitor will attack the cancer cell’s DNA repair mechanisms via at least two orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA1/2 and/or other DNA repair defects. An innovative component of our proposal is that we have developed in silico the first small-molecule inhibitory chemotype which inhibits both PI-3K and PARP activity simultaneously (e.g. SRX3128; preliminary results). We have demonstrated “proof of concept” that SRX3128: 1) augments cell death following DNA damage 2) Inhibits both targets DNA repair and PI-3K simultaneously in the same tumor cell and 3) displays less toxicity in normal cells compared with individual inhibitory chemotypes at equivalent potency against targets. The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently inhibit DNA repair via multiple orthogonal mechanisms and chemo-radiosensitive tumor cells to DNA damaging agents. This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound(s) to a clinical candidate: Aim (Task) #1. Develop a dual PI-3 kinase/PARP inhibitor. Aim (Task) #2. Develop a predictive computational PARP model for the in silico docking of designed compounds. Approach: Improve in silico PARP-ligand fit parameters of our PARP model until a high PARP-docking/PARP- assay-inhibition correlation is achieved. Aim (Task) #3. Determine therapeutic window for dual PI-3K/PARP inhibition. Approach: Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells (NSCs) when exposed to single PARP inhibitor or PI-3K inhibitor versus dual PARP/PI-3K inhibition conditions. The significance of this research is it will greatly expand the reach of PARP inhibition into BRCA-proficient cancers. This innovative approach attacks cancer using two distinct proven mechanisms with a single compound challenging the one-drug one-target dogma.