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。是由Caltech建立的，用于开发针对新癌症的小分子药物 靶标DNA2治疗三阴性乳腺癌（TNBC）。我们花了几十年来揭示 DNA2 ATP运动驱动核酸酶活性在缓解复制叉处的复制应力并进行 修理叉子塌陷以双链断裂（DSB）。我们的科学前提是DNA2是阿喀琉斯的脚跟 癌细胞增殖的，我们可以使用小分子抑制剂靶向它。因为被激活 癌基因和灭活的肿瘤补充剂导致复制应力和双链断裂（DSB），A 肿瘤的子集取决于DNA2以支持其生长。 乳腺癌（BC），2021年预计在美国有超过281,000例新病例和44,000例死亡， 是女性的第二大癌症。卑诗省是一种异源性疾病，有10-15％的病例为 分类为基本类似，主要是TNBC。 TNBC具有人类BC亚型的最差预后，更多 在40岁以下的年轻妇女，特别是非裔美国妇女中流行。结果不佳的一个因素是 靶向疗法的缺乏。我们对DNA2作为TNBC目标的关注与TNBC的15-20％一致 病例缺乏乳腺癌易感性基因BRCA1/2在对抗中至关重要 复制应力。我们已经证明DNA2对于TNBC中的基因组稳定性和存活很重要 细胞系。 DNA2抑制剂的治疗指数可能是由于内在的固有水平较高 与正常细胞（即肿瘤细胞敏化）相比，具有突变的癌基因或肿瘤补充的肿瘤， 以及正常细胞中存在的替代修复途径的存在（即保护正常细胞免受 DNA2功能的丧失）。我们通过比较正常/二倍体中DNA2I的效力，通过比较了这一实验表明 细胞模型以及体外癌细胞系。 我们先前已经描述了小分子DNA2抑制剂，并证明了它们的生化 乳腺癌细胞中体外的选择性和作用方式。这个阶段我奖将使我们能够追求两个 里程碑：命中率开发和体内效率的演示。 AIM 1专注于命中率 最先进的DNA2抑制剂（DNA2I）支架的优化。目标是改善类似毒品的特性 DNA2生化和细胞效力，而不会丧失目标特异性，导致NM铅分子 对其他DNA修复酶的活性最小活性的细胞效力，并有希望的体外ADME特性 支持体内测试。 AIM 2将评估鼠标PK研究中的铅化合物，以确认体内暴露 然后进行体内小鼠TNBC特征研究。目标是在 体内效率。成功完成该项目将使我们能够促进领导优化研究和 II期进一步的药理学，辅助研究（GLP，PK和毒理学）。将DNA2i推到诊所 将为TNBC患者提供急需的治疗选择。