Development of novel, targeted small molecule inhibitors of DNA repair in high unmet need tumors-TNBC

开发新型靶向小分子 DNA 修复抑制剂，用于高度未满足需求的肿瘤 - TNBC

• 批准号: 10480460
• 负责人: Judith L CAMPBELL
• 金额: $ 39.72万
• 依托单位: DNATWO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480460
• 关键词: ATR gene; Adsorption; Affect; African American; Animals; Award; Biochemical; Biological Assay; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer cell line; Cancer-Predisposing Gene; Cell Proliferation; Cell model; Cells; Cessation of life; Chronic; Clinic; Clinical; Computer Models; DNA Repair; DNA Repair Enzymes; DNA biosynthesis; DNA replication fork; Data; Deoxyribonucleases; Dependence; Development; Diploid Cells; Disabled Persons; Disease; Dose; Drug Targeting; Drug resistance; Epidermal Growth Factor; Estrogens; Excretory function; Exhibits; Genome Stability; Genomic Instability; Genomics; Goals; Growth; Hormone Receptor; Human; In Vitro; Lead; Legal patent; MDA MB 231; Malignant Neoplasms; Metabolism; Modeling; Motor; Mus; Mutate; Normal Cell; Oncogenes; Oncogenic; Oral; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Poly(ADP-ribose) Polymerases; Progesterone; Prognosis; Property; Proteins; Recurrence; Resistance; Rivers; Role; Skin Cancer; Small Business Technology Transfer Research; Specificity; Technology; Therapeutic; Therapeutic Index; Toxicology; Triage; Tumor Suppressor Proteins; Woman; Xenograft Model; Xenograft procedure; acquired drug resistance; base; brca gene; cancer cell; cancer subtypes; cancer therapy; cell transformation; design; early onset; helicase; homologous recombination; improved; in vivo; in vivo evaluation; inhibitor; innovation; knock-down; lead optimization; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel; novel strategies; nuclease; overexpression; programmed cell death ligand 1; programs; repaired; replication stress; scaffold; small molecule; small molecule inhibitor; success; synergism; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; young woman

DNATWO, Inc. was founded out of Caltech to develop small molecule drugs targeting a new cancer target, DNA2, to treat triple-negative breast cancer (TNBC). We have spent decades unraveling the role of the DNA2 ATP-motor driven nuclease activity in relieving replication stress at the replication fork and carrying out repair at forks collapsed to double strand breaks (DSBs). Our scientific premise is that DNA2 is the Achilles’ heel of cancer cell proliferation, and that we can target it using small molecule inhibitors. Because activated oncogenes and inactivated tumor suppressors lead to replication stress and double strand breaks (DSB), a subset of tumors is dependent on DNA2 to support their growth. Breast cancer (BC), with over 281,000 new cases and 44,000 deaths expected in 2021 in the USA, is the second most common cancer in women. BC is a heterogenous disease, with 10-15% of cases being classified as basal like, predominantly TNBC. TNBC has the worst prognosis of human BC subtypes and is more prevalent in young women under 40, particularly African American women. A factor in the poor outcome is the dearth of targeted therapies. Our focus on DNA2 as a target in TNBC is consistent with 15-20% of TNBC cases being deficient in the breast cancer susceptibility genes BRCA1/2 critically important in combating replication stress. We have demonstrated that DNA2 is important for genome stability and survival in TNBC cell lines. A therapeutic index for DNA2 inhibitors is likely due to the high intrinsic levels of replication stress in tumors with mutated oncogenes or tumor suppressors as compared to normal cells (i.e. sensitizing tumor cells), as well as the presence of alternative repair pathways present in normal cells (i.e. protecting normal cells from loss of DNA2 function). We have shown this experimentally by comparing potency of DNA2i in a normal/diploid cell model as well as cancer cell lines in vitro. We have previously described small molecule DNA2 inhibitors and demonstrated their biochemical selectivity and mode of action in vitro in breast cancer cells. This Phase I award will allow us to pursue two milestones: Hit-to-Lead development and the demonstration of in vivo efficacy. Aim 1 focuses on Hit-to-Lead optimization on the most advanced DNA2 inhibitor (DNA2i) scaffolds. The goal is to improve drug-like properties and DNA2 biochemical and cellular potency without loss of target specificity, resulting in lead molecules with nM potency in cells with minimum activity against other DNA repair enzymes, and promising in vitro ADME properties to support in vivo testing. Aim 2 will evaluate lead compounds in a mouse PK study to confirm in vivo exposure followed by an in vivo mouse TNBC xenograft study. The goal is a lead DNA2i molecule with demonstrated in vivo efficacy. Successful completion of this project will allow us to advance to lead optimization studies and further pharmacology, IND-enabling studies (GLP, PK, and toxicology) in Phase II. Advancing DNA2i to the clinic will provide an urgently needed treatment option for TNBC patients.

DNATWO, Inc. 在加州理工学院成立，致力于开发针对新癌症的小分子药物 我们花了几十年的时间来阐明 DNA2 治疗三阴性乳腺癌 (TNBC) 的作用。 DNA2 ATP 电机驱动的核酸酶活性可缓解复制叉处的复制应激并执行 修复双链断裂 (DSB) 的叉子 我们的科学前提是 DNA2 是致命弱点。 癌细胞增殖，我们可以使用小分子抑制剂来靶向它。 癌基因和失活的抑癌基因会导致复制应激和双链断裂（DSB）， 部分肿瘤依赖 DNA2 来支持其生长。 乳腺癌 (BC)，预计 2021 年美国将有超过 281,000 例新发病例和 44,000 例死亡， BC 是女性第二常见的癌症，是一种异质性疾病，其中 10-15% 的病例是这种疾病。 分类为基础样，主要为 TNBC，其预后在人类 BC 亚型中最差，且更为严重。 常见于 40 岁以下的年轻女性，尤其是非裔美国女性，这是导致结果不佳的一个因素。 缺乏靶向治疗。我们对 DNA2 作为 TNBC 靶标的关注与 15-20% 的 TNBC 一致。 缺乏乳腺癌易感基因 BRCA1/2 的病例对于对抗乳腺癌至关重要 我们已经证明 DNA2 对于 TNBC 中的基因组稳定性和存活很重要。 DNA2 抑制剂的治疗指数可能是由于细胞系中高内在水平的复制应激。 与正常细胞相比，具有突变癌基因或肿瘤抑制基因的肿瘤（即致敏肿瘤细胞）， 以及正常细胞中存在替代修复途径（即保护正常细胞免受 DNA2 功能丧失）我们通过比较正常/二倍体中 DNA2i 的效力通过实验证明了这一点。 细胞模型以及体外癌细胞系。 我们之前描述过小分子 DNA2 抑制剂并展示了它们的生物化学 乳腺癌细胞的体外选择性和作用方式 这一第一阶段的奖项将使我们能够追求两个目标。 里程碑：Hit-to-Lead 开发和体内功效演示 目标 1 重点关注 Hit-to-Lead。 对最先进的 DNA2 抑制剂 (DNA2i) 支架进行优化，目标是改善药物样特性。 和 DNA2 生化和细胞效力，而不损失目标特异性，从而产生具有 nM 的先导分子 在细胞中对其他 DNA 修复酶的活性最低，并且具有良好的体外 ADME 特性 为了支持体内测试，Aim 2 将在小鼠 PK 研究中评估先导化合物，以确认体内暴露。 随后进行了体内小鼠 TNBC 异种移植研究，目标是在 该项目的成功完成将使我们能够推进领先的优化研究和研究。 II 期进一步的药理学、 IND 支持研究（GLP、PK 和毒理学）。 将为TNBC患者提供急需的治疗选择。