Dual PI3K/BRD4 Inhibitory Chemotype for Maximum Inhibition of MYC and Cancer

抑制关键的癌症促进转录因子MYC(c-MYC和MYCN)的需求尚未得到满足 它们作用于许多细胞受体和信号转录通路的下游，激活癌细胞的基因 耐药性、肿瘤生长与抗肿瘤免疫调控。迄今为止，MYC的小分子抑制剂 仍然难以捉摸。在我们的初步数据中，我们开发了一种先导化合物SF2523，它显示出 阻断PI-3激酶(PI-3K)及其主要调控因子对MYC的正交抑制活性 表观遗传机制，BRD4。在这里，我们开始开发SF2523和其他化学类型，通过额外的 在硅晶体结构和核磁共振分析和优化中为高级临床前研究做准备 Myc依赖性肿瘤的治疗应用。 转录因子MYC(c-MYC和MYCN)在肿瘤的生长、增殖、生存、 以及最近在控制抗肿瘤免疫方面的研究。它在大多数人类的一个亚群中过度表达 癌症导致对PI-3K和其他信号通路抑制剂产生耐药性。MYC和PI-3K都很好- 已确定的癌蛋白是大量肿瘤类型的驱动因素。此外，BRD4是 迅速成为转录组和癌细胞耐药的主要表观遗传调节因子 激酶抑制。因此，在癌症生物学领域已经达成了普遍共识，即抑制BRD4 和/或MYC在多种癌症中应该被证明是有益的，在这些癌症中，MYC是肿瘤细胞的既定调节因子 转变和抵抗。我们的创新方法以我们的中心假设为中心，即双重PI- 3K/BRD4抑制剂SF2523将通过抑制PI-3K促进MYC的降解，从而有效地抑制MYC的活性 并通过抑制BRD4来阻断MYC的转录活性。我们的初步数据支持我们在这方面的成功 我们解决了SF2523在BRD4活性中心的晶体结构，并测定了其结构活性 通过验证的分子模拟研究和设计的围绕双PI-3K/BRD4抑制剂的关系(SAR) 证明了我们的双靶向单一抑制剂的安全性与使用两种药物的累积毒性 不同的抑制剂。我们的初步研究支持我们的具体目标，包括：1)优化 围绕我们的晶体结构和核磁共振分析(目标2)构建的双重抑制化学型(目标1)与 2)评价每种口服优化化疗方案的安全性、PK/PD模型和抗肿瘤效果(目标3)。 我们建议的目标是推进这种新型双重PI-2的临床前开发和验证。 3K/BRD4抑制剂SF2523或其衍生物作为抗PI-3K/MYC驱动的恶性肿瘤的最终候选药物 死亡率高，如肝细胞癌和头颈部鳞状细胞癌 (SCCHN)，并获得最终开发的优化候选口腔。此外，我们的目标是寻求确定 PI-3K和MYC肿瘤信号将在我们迈向I期临床时定义对SF2523的敏感性 这种“首屈一指”的双重PI-3K/BRD4抑制化疗药物个体化治疗的试验。

There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN) that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance, tumor growth and the control of antitumor immunity. To date, small molecule inhibitors of MYC have remained elusive. In our preliminary data, we developed a lead compound, SF2523 which displays potent orthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator of epigenetic machinery, BRD4. Herein, we set out to develop SF2523 and other chemotypes through additional in silico crystal structure and NMR analysis and optimization in preparation for advanced preclinical studies for therapeutic application in Myc dependent cancers. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and more recently in the control of antitumor immunity. It is overexpressed in a subgroup of most human cancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well- established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover, BRD4 is rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibition. Therefore, there is general consensus in the cancer biology arena that inhibition of BRD4 and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI- 3K/BRD4 inhibitor, SF2523, will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibition AND block MYC transcriptional activity via BRD4 inhibition. Our preliminary data supports our success in that we solved the crystal structure of SF2523 in the active site of BRD4 and determined the structure activity relationships (SAR) around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using two separate inhibitors. Our preliminary studies support our specific aims which include: 1) SAR to optimize the dual inhibitory chemotype (Aim 1) built around our crystal structure and NMR analyses (Aim 2) in parallel with 2) the evaluation of safety, PK/PD modeling and antitumor efficacy of each oral optimized chemotype (Aim 3). The objective of our proposal is to advance the preclinical development and validation of this novel dual PI- 3K/BRD4 inhibitor, SF2523 or its derivative as a final drug candidate against PI-3K/MYC-driven malignancies with high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck (SCCHN) and obtain an optimized oral candidate for final development. Moreover, our aims seek to identify PI-3K and MYC tumor signatures which will define sensitivity to SF2523 as we move toward a Phase I clinical trial of this “first in class” dual PI-3K/BRD4 inhibitory chemotype for individualized cancer therapeutics.