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

Culnexin Therapeutics LLC是一家开发一流小分子药物的初创生物技术公司 其抑制CUL 4A泛素连接酶作为三阴性乳腺癌（TNBC）的治疗。乳腺癌是 这是妇女的第二大死因，每8名妇女中就有1人在其一生中被诊断出这种疾病。TNBC 占每年32.3万新病例的约10-15%，不成比例地影响年轻女性， 并且是一种更侵袭性的疾病，对其不存在有效的/靶向的治疗。本STTR的目标是 通过开发小分子CUL 4A抑制剂来解决TNBC患者缺乏靶向治疗的问题。 Culnexin创始人周鹏波博士在威尔康奈尔医学发现，CUL 4A过表达， （CUL 4A高）驱动多种癌症类型，是患者生存的不良预后指标。CUL 4A高 TNBC依赖于高水平的CUL 4A表达，并且CUL 4A的遗传失活导致选择性的CUL 4A表达。 杀死CUL 4A高肿瘤，同时使健康组织不受影响。重要的是，CUL 4A失活还导致 细胞毒性T细胞和NK细胞大量浸润到肿瘤中，使CUL 4A成为两种靶向治疗的独特靶标。 干预和免疫肿瘤治疗。我们已经进行了240，000的高通量筛选， 化合物和鉴定/验证的能够选择性抑制CUL 4A的多重命中化合物。结构- 活性关系（SAR）分析导致早期先导化合物的产生， 在体外和体内，具有纳摩尔亲和力和精细的抗TNBC活性。Culnexin的长期目标是 通过为TNBC患者提供一种机制上新颖的双重作用癌症， 疗法在这个I期STTR中，我们将开发比我们目前的化合物更有效的CUL 4A抑制剂。 我们将（1）进行结构-功能分析，以获得一组抑制CUL 4A的先导化合物;（2） 确定体内DMPK/ADMETox特性和CUL 4A抑制剂的抗肿瘤功效， TNBC的临床相关模型。这项工作将开发更多的药物样CUL 4A抑制剂，并验证它们 在适当的TNBC模型中。在第二阶段，我们将生成先进的临床前数据，以便提交 向FDA提交研究性新药（IND）申请。我们的抗CUL 4A药物代表了一流的 治疗每年诊断的47%的CUL 4A高肿瘤TNBC患者。我们预期我们的药物 根据FDA的规定，由于高度新颖的作用机制和未满足的需求，将有资格获得快速通道。我们 计划在第二阶段STTR研究期间与大型制药公司合作，将我们的产品推向市场。

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, we will develop CUL4A inhibitors more effective than our current compounds. We will (1) carry out structure-function analysis to obtain a panel of lead compounds 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.