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：
10325861
负责人：
SCOTT D ELIASOF
金额：
$ 40万
依托单位：
CULNEXIN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325861
关键词：
Address Affect Affinity Animals Antineoplastic Agents Biological Assay Biological Availability Biotechnology Brain Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy CUL4A gene Cause of Death Cell Membrane Permeability Cell model Cells Colorectal Neoplasms Cytotoxic T-Lymphocytes Data Diagnosis Disease Estrogen Receptor alpha Excision Fluorescence Generations Genetic Goals Immune Immunooncology Immunotherapy In Vitro Induction of Apoptosis Infiltration Intervention Investigational New Drug Application Lead Liver Lung MDA-MB-468 Malignant Neoplasms Maximum Tolerated Dose Medical Medicine Metabolic Modeling Mus Natural Killer Cells Non-Malignant Oncogenic Operative Surgical Procedures Organ Outcome Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Prognostic Marker Property Radiation STAT3 gene Series Small Business Technology Transfer Research Solid Neoplasm Structure Structure-Activity Relationship Survival Rate Therapeutic Tissues Toxic effect Woman Work Xenograft Model analog base cancer therapy cancer type chemical stability chemotherapy clinically relevant commercial application drug candidate high throughput screening improved outcome in vitro activity in vivo inhibitor/antagonist malignant breast neoplasm nanomolar novel overexpression pre-clinical precision oncology receptor small molecule small molecule inhibitor standard of care targeted treatment triple-negative invasive breast carcinoma tumor tumor microenvironment ubiquitin ligase 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, 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.

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。在此阶段I STTR中，我们将开发CUL4A抑制剂比目前的化合物更有效。我们将（1）进行结构功能分析，以获取一组铅化合物以进行CUL4A抑制；（2）确定铅CUL4A抑制剂在体内DMPK/ADMETOX特性和抗肿瘤效率 TNBC的临床相关模型。这项工作将开发更多类似药物的Cul4a抑制剂并验证它们在适当的TNBC模型中。在第二阶段，我们将生成高级临床前数据，以便提交调查新药（IND）应用于FDA。我们的抗Cul4a药物代表着第一类每年诊断出47％的CUL4AHIGH肿瘤患者的TNBC患者的治疗。我们期待我们的毒品由于行动和未满足的需求的高度新颖的机制，将在FDA规则下符合FDA规则的资格。我们计划通过在II阶段STTR研究中与大型制药公司合作将我们的产品推向市场。