Small Molecule CUL4 Inhibitors as Dual Precision Oncology and Immuno-Oncology Drugs

库尔尼辛治疗有限责任公司是一家初创生物技术公司，开发一流的小分子药物 抑制CUL4A泛素连接酶作为三阴性乳腺癌(TNBC)的治疗。乳腺癌是 这是女性的第二大死因，每8名女性中就有1人在有生之年被确诊。TNBC 约占每年32.3万新病例的10%-15%，对年轻女性的影响不成比例， 是一种更具侵袭性的疾病，目前还没有有效的/有针对性的治疗方法。此STTR的目标是 通过开发小分子CUL4A抑制剂来解决TNBC患者缺乏靶向治疗的问题。 Weill Cornell Medicine的Culnexin创始人周鹏波博士发现CUL4A过度表达 (CUL4AHigh)导致多种癌症类型，是患者生存的不良预后指标。CUL4AHigh TNBCs对高水平的CUL4A表达上瘾，CUL4A的基因失活导致选择性 杀死CUL4A高肿瘤，而健康组织不受影响。重要的是，CUL4A失活也会导致 大量细胞毒性T和NK细胞渗透到肿瘤中，使CUL4A成为这两个靶点的独特靶点 干预和免疫肿瘤治疗。我们已经进行了24万个高通量筛查 化合物，并鉴定/验证了能够选择性抑制CUL4A的多种命中化合物。结构- 活度关系(SAR)分析导致早期铅化合物的生成 纳摩尔亲和力和良好的体内外抗TNBC活性。库尔尼辛的长期目标是 通过为TNBC患者提供一种机械上新颖的双重作用癌症来改善患者的预后 心理治疗。在第一阶段STTR行政补充中，我们将开发更多PA9类似CUL4A抑制剂 比我们目前的化合物更有效。我们将(1)进行结构-功能分析，以获得一块铅板 PA9类似物对CUL4A的抑制作用；(2)测定DMPK/ADMETox的体内性质和抗肿瘤作用 铅CUL4A抑制剂在临床相关的TNBC模型中的疗效。这项工作将开发出更多的类药物 CUL4A抑制剂，并在适当的TNBC模型中验证它们。在第二阶段，我们将生成高级 临床前数据，以便向FDA提交研究新药(IND)申请。我们的抗CUL4A 对于47%的被诊断为CUL4A高肿瘤的TNBC患者来说，药物是一流的治疗方法 年。我们预计，根据FDA的规定，我们的药物将有资格进入Fast Track，因为 行动和未得到满足的需求。我们计划在第二阶段通过与大型制药公司合作将我们的产品推向市场。 STTR研究。

Culnexin Therapeutics LLC is a startup biotechnology company developing first-in-class small molecule drugs that inhibit the CUL4A ubiquitin ligase as a treatment for triple negative breast cancer (TNBC). Breast cancer is the second leading cause of death for women, with 1 in 8 women diagnosed within her lifetime. TNBC comprises approximately 10-15% of the 323K new cases annually, disproportionately affects younger women, and is a more aggressive disease for which no effective/targeted treatments exist. The goal of this STTR is to address the lack of targeted treatment for patients with TNBC by developing small molecule CUL4A inhibitors. Culnexin founder Dr. Pengbo Zhou at Weill Cornell Medicine discovered that CUL4A overexpression (CUL4Ahigh) drives multiple cancer types and is a poor prognostic indicator of patient survival. CUL4Ahigh TNBCs are addicted to high levels of CUL4A expression, and genetic inactivation of CUL4A leads to selective killing of CUL4Ahigh tumors while leaving healthy tissue unaffected. Importantly, CUL4A inactivation also causes massive infiltration of cytotoxic T and NK cells into tumors, making CUL4A a unique target for both targeted intervention and immuno-oncological therapy. We have conducted a high throughput screen of 240,000 compounds and identified/validated multiple hit compounds capable of selective CUL4A inhibition. Structure- activity relationship (SAR) analysis led to the generation of early lead compounds that displayed low nanomolar affinity and exquisite anti-TNBC activities in vitro and in vivo. The long-term goal of Culnexin is to improve outcomes for patients with TNBC by providing them with a mechanistically novel, dual-action cancer therapy. In this phase I STTR Administrative Supplement, we will develop PA9 analog CUL4A inhibitors more effective than our current compounds. We will (1) carry out structure-function analysis to obtain a panel of lead PA9 analogs for CUL4A inhibition; (2) determine the in vivo DMPK/ADMETox properties and anti-tumor efficacies of lead CUL4A inhibitors in clinically relevant models of TNBC. This work will develop more drug-like CUL4A inhibitors and validate them in appropriate TNBC models. In Phase II, we will generate advanced preclinical data in order to submit an Investigational New Drug (IND) application to the FDA. Our anti-CUL4A drugs represent a first-in-class treatment for the 47% of TNBC patients with CUL4Ahigh tumors diagnosed each year. We anticipate our drug will qualify for Fast Track under FDA rules due to the highly novel mechanism of action and unmet need. We plan to bring our product to market by partnering with large pharma during phase II STTR studies.