Development of a potent and selective oral ENPP1 inhibitor for oncology

开发用于肿瘤学的有效且选择性口服 ENPP1 抑制剂

• 批准号: 10603980
• 负责人: Mohan Rao Kaadige
• 金额: $ 116万
• 依托单位: STINGRAY 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: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603980
• 关键词: Adaptive Immune System; Adenosine; Breast; Breast Cancer Model; CTLA4 gene; Canis familiaris; Cells; Cisplatin; Clinical; Clinical Trials; Cyclic GMP; Cytosol; DNA; Development; Drug Kinetics; Drug resistance; Enzymes; FDA approved; Family member; Funding; Gene Expression; Goals; Growth; Half-Life; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Innate Immune Response; Innate Immune System; Intercept; Laboratories; Lead; Malignant Neoplasms; Modeling; Mus; Neoplasm Metastasis; Oncology; Oral; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Positioning Attribute; Private Sector; Prognosis; Proteins; Radiation; Rattus; Regimen; Rivers; STING agonists; Safety; Signal Transduction; Site; Small Business Innovation Research Grant; Stimulator of Interferon Genes; Surface; Tablets; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Toxicology; Work; adaptive immune response; anti-cancer; arm; base; cancer cell; cancer therapy; cancer type; cell motility; chemotherapy; data modeling; dosage; efficacy evaluation; extracellular; first-in-human; inflammatory milieu; inhibitor; malignant breast neoplasm; mouse model; novel; overexpression; pharmacokinetics and pharmacodynamics; phosphoric diester hydrolase; plasma cell membrane glycoprotein PC-1; pre-clinical research; preclinical development; preclinical evaluation; preclinical study; prevent; programmed cell death protein 1; programs; pyrophosphatase; research and development; side effect; small molecule inhibitor; standard of care; stingray; success; synergism; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

ABSTRACT Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator of INterferon Genes) pathway is necessary to elicit potent anti-cancer innate immune responses. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the STING pathway's only known direct negative regulator expressed in many tumor types, and, when it is overexpressed, tumors show limited efficacy to front-line therapies. Such as, in triple-negative breast cancer (TNBC), high ENPP1 expression is associated with drug resistance and poor prognosis. If a safe and efficacious ENPP1 inhibitor were available, it would have widespread utility for multiple cancer types and, if used in combination with other cancer therapies, may enhance their performance. Towards this end, we have developed an orally bioavailable potent small-molecule inhibitor of ENPP1 called SR-8541A. It inhibits hENPP1 activity with an IC50 of 3.6 nM (Ki=1.9 nM) and demonstrates robust selectivity. We have established that it activates the STING pathway, promotes immune cell infiltration, and inhibits cancer spheroid growth. Furthermore, in syngeneic tumor mouse models, SR-8541A demonstrates a synergistic effect with radiation, and a preliminary study also shows synergy with checkpoint inhibitors. To date, we have completed preclinical development activities on SR-8541A that include API development and manufacturing, stability, pharmacokinetics, tolerability, and preliminary toxicology (mouse, rat, dog). The overall goal of this Direct to Phase II SBIR application is to complete non-GLP and GLP preclinical studies for our lead molecule SR-8541A with TNBC as our initial focus. In Aim 1, we will evaluate the efficacy of SR-8541A in combination with FDA-approved drug regimens (e.g., cisplatin, anti-mCTLA-4, anti-mPD-1, PARP inhibitor) in 4T-1 and EMT-6 breast cancer mouse models. In Aim 2, we will conduct IND enabling GLP toxicology study in dogs as the rat GLP study is complete. In Aim 3, we will develop and manufacture cGMP clinical-grade tablets necessary to conduct a Phase 1 clinical trial. Direct to Phase II SBIR success will result in the completion of the required preclinical studies to seek IND acceptance for a first-in-human Phase I clinical trial and to engage with private-sector investors in funding clinical trials in TNBC. If SR-8541A is approved for patient use, it would be the first-in-class molecule to modulate the innate immune system, expanding the benefits of immunotherapy to more patients.

摘要 令人信服的证据表明，小心和治疗相关的激活STING（STimulator of 干扰素基因）途径是引发有效的抗癌先天免疫应答所必需的。外核苷酸 焦磷酸酶/磷酸二酯酶1（ENPP 1）是STING途径唯一已知的直接负调节因子 在许多肿瘤类型中表达，并且当其过表达时，肿瘤对一线治疗的功效有限。 治疗例如，在三阴性乳腺癌（TNBC）中，ENPP 1高表达与药物治疗相关。 耐药和预后差。如果有一种安全有效的ENPP 1抑制剂， 广泛应用于多种癌症类型，如果与其他癌症疗法联合使用， 他们的表现。为此，我们开发了一种口服生物有效的小分子抑制剂 SR-8541A它抑制hENPP 1活性，IC 50为3.6 nM（Ki=1.9 nM），并证明 强大的选择性。我们已经确定它激活STING途径，促进免疫细胞浸润， 并抑制癌球体生长。此外，在同基因肿瘤小鼠模型中，SR-8541 A证明 与辐射的协同作用，初步研究也显示与检查点抑制剂的协同作用。到 截至目前，我们已完成SR-8541 A的临床前开发活动，包括API开发和 生产、稳定性、药代动力学、耐受性和初步毒理学（小鼠、大鼠、犬）。整体 本直接进入II期SBIR申请的目标是完成我们电极导线的非GLP和GLP临床前研究 分子SR-8541 A与TNBC作为我们的初始焦点。在目标1中，我们将评估SR-8541 A在以下方面的疗效： 与FDA批准的药物方案（例如，顺铂、抗mCTLA-4、抗mPD-1、PARP抑制剂） 4 T-1和EMT-6乳腺癌小鼠模型。在目标2中，我们将开展IND使GLP毒理学研究， 犬，因为大鼠GLP研究已完成。在目标3中，我们将开发和生产cGMP临床级片剂 进行第一阶段临床试验。直接到第二阶段SBIR的成功将导致完成 要求进行临床前研究，以寻求IND接受首次人体I期临床试验，并与 私营部门投资者资助TNBC的临床试验。如果SR-8541 A被批准用于患者， 第一个调节先天免疫系统的分子，扩大了免疫治疗的益处， 更多的病人