期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 12, 页码 8142-8160出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02144
关键词
-
资金
- German Research Foundation (DFG) [397659447, JO 1473/1-3]
- SGC [1097737]
- AbbVie
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond
- Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN] [875510]
- Janssen
- Merck KGaA (aka EMD in Canada and US)
- Merck & Co (aka MSD outside Canada and US)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- German translational cancer network DKTK
- Frankfurt Cancer Institute (FCI)
- European Union [730872]
Salt-inducible kinases (SIKs) are crucial metabolic regulators, with their imbalance linked to various cancers. Researchers have optimized a kinase inhibitor to target SIK specifically, providing a potential new approach for cancer therapy by combining SIK inhibitors with traditional chemotherapeutic agents like paclitaxel.
Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据