Development of a potent and selective oral ENPP1 inhibitor for oncology

摘要 令人信服的证据表明，小心和与治疗相关的刺痛激活(刺激物) 干扰素基因)途径是诱导强大的抗癌先天免疫反应所必需的。环核苷酸 焦磷酸酶/磷酸二酯酶1(ENPP1)是唯一已知的刺痛途径的直接负调控因子 在许多肿瘤类型中都有表达，当它过度表达时，肿瘤对一线的疗效有限 治疗。例如，在三阴性乳腺癌(TNBC)中，ENPP1高表达与药物有关 耐药，预后差。如果有一种安全有效的ENPP1抑制剂，它将会 广泛适用于多种癌症类型，如果与其他癌症疗法联合使用，可能会增强 他们的表演。为此，我们开发了一种口服生物利用型有效小分子抑制剂。 被命名为SR-8541a的ENPP1。它抑制hENPP1活性，IC50为3.6 nM(Ki=1.9 nM)，并显示 强大的选择性。我们已经确定，它激活了刺痛途径，促进了免疫细胞的渗透， 并抑制癌症球体的生长。此外，在同基因肿瘤小鼠模型中，SR-8541A证明 与辐射有协同作用，初步研究也显示与检查点抑制剂有协同作用。至 到目前为止，我们已经完成了SR-8541A的临床前开发活动，包括原料药开发和 制造、稳定性、药代动力学、耐受性和初步毒理学(小鼠、大鼠、狗)。整体而言 这项Direct to II期SBIR应用的目标是为我们的Lead完成非GLP和GLP临床前研究 分子SR-8541a，以TNBC为初始关注点。在目标1中，我们将评估SR-8541A在 联合FDA批准的药物方案(如顺铂、抗mCTLA-4、抗MPD-1、PARP抑制剂) 4T-1和EMT-6乳腺癌小鼠模型。在目标2中，我们将进行Ind Enable GLP毒理学研究 狗作为大鼠的GLP研究已经完成。在目标3中，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。直接到第二阶段SBIR的成功将导致完成 所需的临床前研究以寻求IND接受第一个人类I期临床试验并参与 私营部门投资者为TNBC的临床试验提供资金。如果SR-8541A被批准用于患者，它将是 一流的分子来调节先天免疫系统，将免疫疗法的好处扩大到 更多的病人。

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.