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

使用双重 PI-3K/PARP 抑制剂最大限度地提高癌症合成致死率

基本信息

批准号：
9255563
负责人：
DONALD DURDEN
金额：
$ 29.97万
依托单位：
SIGNALRX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2017-12-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9255563
关键词：
1-Phosphatidylinositol 3-Kinase Academia Adult Antineoplastic Agents BRCA1 gene Biological Assay Cancer Patient Cell Death Cells Childhood Clinic Clinical Collaborations Computer Simulation DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Defect Development Docking Dose Double Strand Break Repair Drug Combinations Effectiveness Germ-Line Mutation Goals Growth Human Individual Industry Knowledge Lead Legal patent Ligands Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Maximum Tolerated Dose Medical Mission Modeling Molecular Models Morbidity - disease rate Mus Mutate Mutation Neoplasm Metastasis Neuroblastoma Neurons Normal Cell Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Poly(ADP-ribose) Polymerases Proteins Public Health Radiation Tolerance Reporting Research Somatic Mutation Staging Testing Therapeutic Toxic effect Tumor Suppressor Genes Work analog angiogenesis cancer cell cancer stem cell cancer therapy cancer type design disability ds-DNA experience homologous recombination improved inhibitor/antagonist innovation kinase inhibitor loss of function loss of function mutation medulloblastoma molecular modeling mortality mutant neoplastic cell nerve stem cell neuroblastoma cell novel novel therapeutics patient population prevent programs prototype radioresistant radiosensitive research clinical testing response scaffold single molecule small molecule small molecule inhibitor small molecule therapeutics targeted treatment technology development triple-negative invasive breast carcinoma tumor

项目摘要

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.

PARP抑制剂（PARPI）在缺乏BRCA1/2肿瘤抑制剂的肿瘤中特别有效基因，但在BRCA主管肿瘤中活性有限。有未满足的医疗需求需要发展目标将增强BRCA1/2野生型癌症的PARPI活性的治疗剂，并增加化学疗法这些恶性肿瘤中的放射敏性。 BRCA1/2蛋白是同源的重要组成部分重组（HR）双链DNA修复机制。 Parpi的合成致死性来自于防止 HR DNA双链断裂（DSB）修复机制，癌细胞无法克服导致致命的DNA损伤。 PARPI对BRCA1/2缺陷或其他DNA修复的细胞有选择性有毒在一些三重阴性乳腺癌中发现的途径突变。最近的一份报告表明PI-3 激酶（PI-3K）抑制作用会损害BRCA1/2的表达，并且可以将BRCA癌症感知到PARP 抑制。因此，我们在此提案中要检验的中心假设是组合双PI-3K 抑制剂（PI-3KI）/ PARP抑制剂将通过至少两种攻击癌细胞的DNA修复机制正交途径并扩展PARPI临床活动，而不是缺乏BRCA1/2和/或其他缺乏的临床活动 DNA修复缺陷。提案的创新组成部分是我们在Silico开发了第一个小分子抑制化学型，同时抑制PI-3K和PARP活性（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损伤后的死亡2）仅在同一肿瘤中抑制DNA修复和PI-3K的靶标与单个抑制性化学型相比，细胞和3）在正常细胞中的毒性较小针对目标的效力。我们的提议的意义在于我们提供优化的能力有望通过多种正交机制抑制DNA修复的有希望的单抗药物和化学触发敏感的肿瘤细胞对DNA损伤剂。该建议将通过实现以下目的，为II期努力奠定了阶段，以优化预期的双重抑制剂铅临床候选者的化合物：AIM（任务）＃1。开发双PI-3激酶/PARP抑制剂。瞄准（任务）＃2。为设计化合物的硅离对接开发预测计算PARP模型。方法：改进我们的PARP模型的Silico PARP-rigand-fit参数，直到高PARP-docking/parp- 实现了测定抑制相关性。 AIM（任务）＃3。确定双PI-3K/PARP的治疗窗口抑制。方法：比较对神经元癌干细胞与正常神经元干细胞的毒性（NSC）暴露于单个PARP抑制剂或PI-3K抑制剂与双PARP/PI-3K抑制条件时。这项研究的意义在于，它将大大扩展PARP抑制的影响力癌症。这种创新的方法使用两种独特的经过验证的机制攻击癌症复合挑战单选项教条。