TY  - JOUR
AU  - Rak, Marcel
AU  - Tesch, Roberta
AU  - Berger, Lena M
AU  - Shevchenko, Ekaterina
AU  - Raab, Monika
AU  - Tjaden, Amelie
AU  - Zhubi, Rezart
AU  - Balourdas, Dimitrios-Ilias
AU  - Joerger, Andreas C
AU  - Poso, Antti
AU  - Krämer, Andreas
AU  - Elson, Lewis
AU  - Lučić, Aleksandar
AU  - Kronenberger, Thales
AU  - Hanke, Thomas
AU  - Strebhardt, Klaus
AU  - Sanhaji, Mourad
AU  - Knapp, Stefan
TI  - Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily.
JO  - European journal of medicinal chemistry
VL  - 254
SN  - 0009-4374
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2023-00814
SP  - 115347
PY  - 2023
AB  - Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo, which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.
KW  - Kinase inhibitor (Other)
KW  - MR22 (Other)
KW  - MRIA9 (Other)
KW  - SIK (Other)
KW  - Salt-inducible kinase (Other)
KW  - pyrido[2,3-d]pyrimidin-7(8H)-one (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37094449
DO  - DOI:10.1016/j.ejmech.2023.115347
UR  - https://inrepo02.dkfz.de/record/275604
ER  -