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

小分子 CUL4 抑制剂作为双重精准肿瘤学和免疫肿瘤学药物

基本信息

批准号：
10673021
负责人：
Pengbo Zhou
金额：
$ 24.61万
依托单位：
CULNEXIN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673021
关键词：
Address Administrative Supplement Affect Affinity Animals Antineoplastic Agents Binding Biochemical Biological Assay Biological Availability Biophysics Biotechnology Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy CUL4A gene Cause of Death Cell Membrane Permeability Cells Complex Cytotoxic T-Lymphocytes Data Diagnosis Disease Estrogen Receptor alpha Fluorescence Generations Genetic Goals Grant Hand Immune Immunooncology In Vitro Induction of Apoptosis Infiltration Intervention Investigational New Drug Application Lead MDA-MB-468 Maximum Tolerated Dose Medical Medicine Metabolic Modeling Mus Natural Killer Cells Oncogenic Outcome Parents Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Property Resources Russia Small Business Technology Transfer Research Solubility Structure Structure-Activity Relationship Therapeutic Tissues Ubiquitination Ukraine Universities War Water Woman Work Xenograft Model Xenograft procedure analog base building materials cancer therapy cancer type chemical stability chemical synthesis clinically relevant cost drug candidate high throughput screening improved improved outcome in vitro activity in vivo inhibitor malignant breast neoplasm medical schools nanomolar novel overexpression pre-clinical precision oncology prognostic indicator receptor scale up small molecule targeted treatment triple-negative invasive breast carcinoma tumor tumor diagnosis tumor microenvironment ubiquitin ligase water solubility young woman

项目摘要

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.

Culnexin Therapeutics LLC 是一家开发一流小分子药物的初创生物技术公司抑制 CUL4A 泛素连接酶作为三阴性乳腺癌 (TNBC) 的治疗方法。乳腺癌是女性死亡的第二大原因，八分之一的女性在其一生中被诊断出来。三全国广播公司约占每年 323K 新病例的 10-15%，尤其影响年轻女性，并且是一种更具侵袭性的疾病，尚无有效/有针对性的治疗方法。该 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。 Culnexin 创始人、威尔康奈尔医学院周鹏波博士发现 CUL4A 过度表达 (CUL4Ahigh) 会导致多种癌症类型，并且是患者生存的不良预后指标。 CUL4A高 TNBC 对高水平的 CUL4A 表达上瘾，CUL4A 的基因失活导致选择性杀死 CUL4Ahigh 肿瘤，同时保持健康组织不受影响。重要的是，CUL4A 失活还会导致细胞毒性 T 细胞和 NK 细胞大量浸润到肿瘤中，使 CUL4A 成为两种靶向药物的独特靶点干预和免疫肿瘤治疗。我们进行了 240,000 次高通量筛选化合物并鉴定/验证了能够选择性抑制 CUL4A 的多重命中化合物。结构- 活性关系（SAR）分析导致了早期先导化合物的产生，这些化合物表现出低纳摩尔亲和力和出色的体外和体内抗 TNBC 活性。 Culnexin 的长期目标是通过为 TNBC 患者提供一种机制新颖的双重作用癌症来改善他们的治疗结果治疗。在本期 STTR 行政补充中，我们将更多地开发 PA9 类似物 CUL4A 抑制剂比我们现有的化合物更有效。我们将（1）进行结构功能分析以获得铅面板用于抑制 CUL4A 的 PA9 类似物； (2)测定体内DMPK/ADMETox特性及抗肿瘤作用主要 CUL4A 抑制剂在 TNBC 临床相关模型中的疗效。这项工作将开发更多类似药物的 CUL4A 抑制剂并在适当的 TNBC 模型中对其进行验证。在第二阶段，我们将产生先进的临床前数据，以便向 FDA 提交研究性新药 (IND) 申请。我们的抗 CUL4A 对于 47% 诊断为 CUL4Ahigh 肿瘤的 TNBC 患者来说，药物代表了一流的治疗方法年。由于高度新颖的机制，我们预计我们的药物将符合 FDA 规则的快速通道资格行动和未满足的需求。我们计划在第二阶段与大型制药公司合作，将我们的产品推向市场 STTR 研究。