TY  - INPR
A1  - Tesch, Roberta
A1  - Rak, Marcel
A1  - Raab, Monika
A1  - Berger, Lena Marie
A1  - Kronenberger, Thales
A1  - Jörger, Andreas C.
A1  - Berger, Benedict-Tilman
A1  - Abdi, Ismahan
A1  - Hanke, Thomas
A1  - Poso, Antti
A1  - Strebhardt, Klaus
A1  - Sanhaji, Mourad
A1  - Knapp, Stefan
T1  - Structure-based design of selective salt-inducible kinase (SIK) inhibitors
T2  - bioRxiv
N2  - Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. 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 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.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72876
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-728764
IS  - 2021.04.08.439011
ER  -