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

基本信息

批准号：
10705273
负责人：
Mohan Rao Kaadige
金额：
$ 83.62万
依托单位：
STINGRAY THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
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/10705273
关键词：
Adaptive Immune System Adenosine Agonist Binding Biological Availability 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 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 Poly(ADP-ribose) Polymerase Inhibitor Positioning Attribute Private Sector Prognosis Proteins Radiation Rattus Regimen 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 cancer cell cancer therapy cancer type cell motility chemotherapy data modeling dosage efficacy evaluation extracellular first-in-human immune cell infiltrate inflammatory milieu inhibitor malignant breast neoplasm manufacture 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 side effect small molecule inhibitor standard of care stingray success synergism triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

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.

抽象的令人信服的证据表明，仔细且与治疗相关的 STING（STimulator 干扰素基因）途径对于引发有效的抗癌先天免疫反应是必要的。外核苷酸焦磷酸酶/磷酸二酯酶 1 (ENPP1) 是 STING 通路唯一已知的直接负调节因子在许多肿瘤类型中表达，当它过度表达时，肿瘤的一线疗效有限疗法。例如，在三阴性乳腺癌（TNBC）中，ENPP1 高表达与药物相关耐药，预后不良。如果有一种安全有效的 ENPP1 抑制剂可用，广泛用于多种癌症类型，如果与其他癌症疗法联合使用，可能会增强他们的表现。为此，我们开发了一种口服生物可利用的强效小分子抑制剂 ENPP1 称为 SR-8541A。它抑制 hENPP1 活性，IC50 为 3.6 nM (Ki=1.9 nM)，并证明鲁棒的选择性。我们已经确定它激活 STING 通路，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-8541A 证明与放射线有协同作用，初步研究也显示与检查点抑制剂有协同作用。到截至目前，我们已经完成了 SR-8541A 的临床前开发活动，包括 API 开发和制造、稳定性、药代动力学、耐受性和初步毒理学（小鼠、大鼠、狗）。整体直接进入 II 期 SBIR 申请的目标是完成我们领先的非 GLP 和 GLP 临床前研究分子 SR-8541A 以 TNBC 为我们最初的焦点。在目标 1 中，我们将评估 SR-8541A 在以下方面的功效：与 FDA 批准的药物治疗方案（例如顺铂、抗 mCTLA-4、抗 mPD-1、PARP 抑制剂）组合 4T-1 和 EMT-6 乳腺癌小鼠模型。在目标 2 中，我们将开展 IND，以促进 GLP 毒理学研究大鼠 GLP 研究已完成。目标3，我们将开发和生产cGMP临床级片剂进行一期临床试验所必需的。直接进入第二阶段 SBIR 的成功将导致完成需要临床前研究来寻求首次人体 I 期临床试验的 IND 接受并参与私营部门投资者资助 TNBC 的临床试验。如果 SR-8541A 被批准供患者使用，则将调节先天免疫系统的一流分子，将免疫疗法的益处扩展到更多患者。