Development of the first-in-class novel dual PI-3K/BRD4 inhibitor SF2523

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 耐药性与肿瘤生长。到目前为止，MYC的小分子抑制剂仍然难以捉摸。在我们的第一阶段 STTR(CA192656)的基础上，我们开发了一种具有强烈的正交抑制作用的先导化合物SF2523 阻断PI-3激酶(PI-3K)和高显性表观遗传调控因子对MYC的抑制作用 机械，BRD4。这项应用的目标将是通过高级临床前开发SF2523 在这项第二阶段STTR提案中的治疗应用研究。 转录因子MYC(c-MYC和MYCN)在肿瘤的生长、增殖、生存、 它在大多数人类癌症的亚群中过度表达，导致对PI-3K和其他 信号通路抑制剂。MYC和PI-3K都是成熟的癌蛋白，已被证实 司机中有大量的肿瘤类型。此外，BRD4正迅速成为一种显性表观遗传学 转录组和癌细胞对激酶抑制的抗性的调节器。因此，有一般的 癌症生物学领域的共识是，抑制BRD4和/或MYC应该证明对多发性骨髓瘤有益 MYC是肿瘤细胞转化和耐药的既定调节因子的癌症。我们的创新 该方法以我们的中心假设为中心，即双重PI-3K/BRD4抑制剂SF2523将有效地抑制MYC 通过抑制PI-3K增强其降解活性和通过BRD4阻断MYC转录活性 抑制力。 我们的第一阶段STTR特殊目标成功地解决了SF2523在活性中心的晶体结构 BRD4，并确定了双PI-3K/BRD4抑制剂的构效关系 验证了分子模拟研究，并证明了我们的双靶向单一抑制剂与 使用两种不同抑制剂的累积毒性。我们成功的第一阶段研究为我们的 选择SF2523作为临床前开发治疗PI-3K/MYC依赖性恶性肿瘤的候选细胞 作为临床开发策略的I期试验。 这一第二阶段提案的意义在于，它将通过临床前开发和 验证这种新型双PI-3K/BRD4抑制剂作为抗PI-3K/MYC驱动的恶性肿瘤的候选药物 高死亡率，例如肝细胞癌和头颈部鳞状细胞癌 (SCCHN)，并通过进一步评估从第一阶段SAR中发现的SF2523类似物来获得备用候选 学习。此外，我们在第二阶段的目标是确定PI-3K和MYC肿瘤信号和一个同伴 诊断方法，将定义对SF2523的敏感性，因为我们正在向FDA注册和 这种“首屈一指”的双重PI-3K/BRD4抑制剂化学类型在癌症治疗中的商业化。

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 and tumor growth. To date, small molecule inhibitors of MYC have remained elusive. In our Phase I STTR (CA192656), 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. The objective of this application will be to develop SF2523 through advanced preclinical studies for therapeutic application in this Phase II STTR proposal. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and 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 blocking MYC transcriptional activity via BRD4 inhibition. Our Phase I STTR Specific Aims successfully solved the crystal structure of SF2523 in the active site of BRD4 and determine the structure activity relationships 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 successful Phase I studies set the stage for our selection of SF2523 as the candidate for preclinical development to treat PI-3K/MYC dependent malignancies in Phase I trials as a clinical development strategy. The significance of this Phase II proposal is that it will advance SF2523 through preclinical development and validate this novel dual PI-3K/BRD4 inhibitor as a 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 a back-up candidate by further evaluation of SF2523 analogs found from Phase I SAR studies. Moreover, our aims in Phase II will identify PI-3K and MYC tumor signatures and a companion diagnostic approach which will define sensitivity to SF2523 as we move toward FDA registration and commercialization of this “first in class” dual PI-3K/BRD4 inhibitor chemotype in cancer therapeutics.