当前位置：
X-MOL 学术
›
ACS Med. Chem. Lett.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-02-19 , DOI: 10.1021/acsmedchemlett.0c00660
Andrew P. Degnan 1 , Godwin K. Kumi 1 , Christopher W. Allard 2 , Erika V. Araujo 2 , Walter L. Johnson 3 , Kurt Zimmermann 2 , Bradley C. Pearce 2 , Steven Sheriff 1 , Alan Futran 1 , Xin Li 1 , Gregory A. Locke 1 , Dan You 4 , John Morrison 1 , Karen E. Parrish 1 , Caitlyn Stromko 1 , Anwar Murtaza 1 , Jinqi Liu 1 , Benjamin M. Johnson 4 , Gregory D. Vite 1 , Mark D. Wittman 4
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-02-19 , DOI: 10.1021/acsmedchemlett.0c00660
Andrew P. Degnan 1 , Godwin K. Kumi 1 , Christopher W. Allard 2 , Erika V. Araujo 2 , Walter L. Johnson 3 , Kurt Zimmermann 2 , Bradley C. Pearce 2 , Steven Sheriff 1 , Alan Futran 1 , Xin Li 1 , Gregory A. Locke 1 , Dan You 4 , John Morrison 1 , Karen E. Parrish 1 , Caitlyn Stromko 1 , Anwar Murtaza 1 , Jinqi Liu 1 , Benjamin M. Johnson 4 , Gregory D. Vite 1 , Mark D. Wittman 4
Affiliation
|
While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.
中文翻译：
口服活性异氟酮类作为造血祖细胞激酶1的强效，选择性抑制剂的发现。
尽管免疫检查点抑制剂的发现已导致多种癌症产生强大而持久的反应，但许多患者对目前可用的治疗方法没有反应。因此，迫切需要鉴定增强免疫介导的肿瘤清除的替代机制。造血祖细胞激酶1（HPK1）是一种丝氨酸-苏氨酸激酶，可作为T细胞受体（TCR）信号的负调节剂，从而减弱免疫反应。在本文中，我们描述了异呋喃酮作为HPK1抑制剂的基于结构的发现。化学型的优化导致效力，选择性，血浆蛋白结合和代谢稳定性的改善，最终鉴定出化合物24。口服24与抗PD1抗体组合，在结直肠癌的同基因肿瘤模型中证明了抗PD1功效的强劲增强。
更新日期：2021-03-11
中文翻译：
口服活性异氟酮类作为造血祖细胞激酶1的强效，选择性抑制剂的发现。
尽管免疫检查点抑制剂的发现已导致多种癌症产生强大而持久的反应，但许多患者对目前可用的治疗方法没有反应。因此，迫切需要鉴定增强免疫介导的肿瘤清除的替代机制。造血祖细胞激酶1（HPK1）是一种丝氨酸-苏氨酸激酶，可作为T细胞受体（TCR）信号的负调节剂，从而减弱免疫反应。在本文中，我们描述了异呋喃酮作为HPK1抑制剂的基于结构的发现。化学型的优化导致效力，选择性，血浆蛋白结合和代谢稳定性的改善，最终鉴定出化合物24。口服24与抗PD1抗体组合，在结直肠癌的同基因肿瘤模型中证明了抗PD1功效的强劲增强。
京公网安备 11010802027423号