Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents

小分子 MYC 降解剂作为新型癌症治疗剂

• 批准号: 10766504
• 负责人: Dennis Liang Fei
• 金额: $ 93.98万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10766504
• 关键词: Adult; Animals; Binding; Biological Assay; Biological Availability; Cancer Patient; Canis familiaris; Cell Culture Techniques; Cell Cycle Progression; Cell Death; Cell Line; Cell Proliferation; Cell physiology; Cellular Assay; Clinical; Clinical Trials; Colorectal Cancer; Dependence; Dissociation; Dominant-Negative Mutation; Dose; Dose Limiting; Drug Kinetics; Genes; Genetic Transcription; Grant; Growth; Guidelines; Homeostasis; Human; In Vitro; Intellectual Property; Lead; Legal patent; Liver Microsomes; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of lung; Marketing; Metabolic; Modeling; Molecular; Molecular Conformation; Monitor; Mus; Neuroblastoma; Oral; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Pre-Clinical Model; Proliferating; Property; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-myc; Protocols documentation; Rattus; Research; Resistance; Role; Safety; Small Business Innovation Research Grant; Solubility; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Toxicokinetics; Toxicology; Transgenic Mice; Translations; Validation; Vendor; Xenograft Model; anti-cancer; aurora kinase A; c-myc Genes; cancer cell; cancer type; canine model; colon cancer cell line; drug candidate; efficacy evaluation; efficacy testing; functional group; improved; inhibitor; mouse model; multicatalytic endopeptidase complex; novel; overexpression; paralogous gene; preclinical development; preclinical safety; safety study; small molecule; tool; transcription factor; tumor growth; tumor xenograft; tumorigenesis

PROJECT SUMMARY/ABSTRACT The MYC family proteins are comprised of three paralogs termed c-myc, N-myc, and L-myc. The MYC proteins play a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such as gene transcription, protein translation, cell cycle progression, and cell death. While N-myc and L-myc drive oncogenesis in a small number of cancer types, the requirement of c-myc is widespread in a broad range of human cancers. MYC protein levels are highly regulated by Aurora A: both c-myc and N-myc bind to Aurora kinase A to “escape” proteasomal degradation. With the support of SBIR Phase I, we have successfully identified novel small molecules that 1). directly target the MYC:Aurora A binding interface, 2). potently degrade both endogenous N-myc and c-myc (henceforth “MYC degraders”), 3). are metabolically stable and orally bioavailable, and 4). are efficacious in inhibiting the growth of tumors dependent on either N-myc or c-myc. For the SBIR Phase II period, we plan to advance pre-clinical development of our MYC degraders with an emphasis on treating c-myc-dependent cancers. We propose two specific aims: Specific Aim 1: Test the efficacy of SSTA-315 across c-myc dependent cancers, while in parallel develop derivative c-myc degraders with improved potency and efficacy. Specific Aim 2: Evaluate the safety profile of SSTA-315 (or an alternative lead MYC degrader) in IND-enabling GLP toxicity studies. Successful completion of the proposed studies will complete IND-enabling safety studies for our lead MYC degrader, preparing for the IND registration with the FDA as the immediate next step. Given that MYC proteins are deregulated in most human cancers, our MYC degraders have potential to impact the lives of millions of cancer patients in U.S. and represent a significant market opportunity.

项目概要/摘要 MYC 家族蛋白由三个旁系同源物组成，称为 c-myc、N-myc 和 L-myc。 MYC 蛋白 通过调节基因等细胞过程，在细胞增殖和肿瘤发生中发挥重要作用 转录、蛋白质翻译、细胞周期进程和细胞死亡。当 N-myc 和 L-myc 驱动时 少数癌症类型的肿瘤发生中，c-myc 的需求广泛存在于多种癌症中 人类癌症。 MYC 蛋白水平受 Aurora A 高度调节：c-myc 和 N-myc 均与 Aurora 结合 激酶 A“逃避”蛋白酶体降解。在 SBIR 第一阶段的支持下，我们成功地确定了 新型小分子 1).直接针对 MYC:Aurora A 绑定接口，2)。有效降解两者 内源性 N-myc 和 c-myc（以下称为“MYC 降解剂”），3)。代谢稳定且口服 生物可利用性，4)。能有效抑制依赖于 N-myc 或 c-myc 的肿瘤生长。 在 SBIR 第二阶段期间，我们计划通过以下方式推进 MYC 降解剂的临床前开发： 重点治疗 c-myc 依赖性癌症。我们提出两个具体目标： 具体目标 1：测试 SSTA-315 在 c-myc 依赖性癌症中的功效，同时进行平行开发 衍生的 c-myc 降解剂具有改进的效力和功效。 具体目标 2：评估 SSTA-315（或替代的主要 MYC 降解剂）在 IND 启用中的安全性 GLP 毒性研究。 成功完成拟议研究将完成我们领先的 MYC 的 IND 安全性研究 degrader，准备下一步向 FDA 进行 IND 注册。鉴于 MYC 蛋白 在大多数人类癌症中，MYC 降解剂均不受管制，我们的 MYC 降解剂有可能影响数百万人的生活 美国的癌症患者，代表着巨大的市场机会。