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创业生物技术公司这抑制了CUL4A泛素连接酶作为三重阴性乳腺癌（TNBC）的治疗方法。乳腺癌是妇女的第二个主要死亡原因，一生中诊断出八分之一的妇女。 TNBC 每年32.3万例新病例中约有10-15％，对年轻妇女的影响不成比例，并且是一种更具侵略性的疾病，不存在有效/有针对性治疗的疾病。这个sttr的目的是通过开发小分子CUL4A抑制剂来解决针对TNBC患者缺乏靶向治疗。 Culnexin创始人Weill Cornell Medicine的Pengbo Zhou博士发现Cul4a过表达（Cul4ahigh）驱动多种癌症类型，并且是患者生存的预后指标。 Cul4ahigh TNBC沉迷于高水平的CUL4A表达，CUL4A的遗传失活导致选择性杀死Cul4ahigh肿瘤的同时使健康组织不受影响。重要的是，CUL4A灭活也会导致将细胞毒性T和NK细胞大量浸润到肿瘤中，使CUL4A成为两个目标的独特目标干预和免疫肿瘤疗法。我们进行了240,000的高吞吐量屏幕化合物并鉴定出/验证的多个命中化合物，能够选择性CUL4A抑制作用。结构- 活动关系（SAR）分析导致早期铅化合物的产生低较低纳摩尔亲和力和精美的体外和体内抗TNBC活性。 Culnexin的长期目标是通过为TNBC患者提供机械新颖的双重动作癌，改善了TNBC患者的预后治疗。在I阶段I STTR管理补充剂中，我们将开发PA9模拟CUL4A抑制剂比我们目前的化合物有效。我们将（1）进行结构功能分析以获取铅面板 PA9类似物用于CUL4A抑制；（2）确定体内DMPK/admetox特性和抗肿瘤铅CUL4A抑制剂在TNBC临床相关模型中的功效。这项工作将发展更多类似毒品 CUL4A抑制剂并在适当的TNBC模型中验证它们。在第二阶段，我们将产生高级临床前数据是为了向FDA提交研究新药（IND）申请。我们的抗cul4a 药物代表了47％的TNBC Cul4Ahigh肿瘤患者的第一类治疗年。我们预计，由于高度新颖的机制行动和未满足的需求。我们计划通过在第二阶段与大型制药公司合作将产品推向市场 STTR研究。