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.

The main protease (M pro , 3CL pro ) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure–activity relationships of novel small-molecule thioesters as SARS-CoV-2 M pro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 M pro inhibition with k inac / K i of 58,700 M –1 s –1 ( K i = 0.0141 μM) and 27,200 M –1 s –1 ( K i = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h , 3i, 3l , 3r , 3v , 3w , and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 M pro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M pro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

Three structures of LXRα (5HJS, 3IPS and 3LOE) and two structures of LXRß (1PQ6 and 1PQ9) were selected based on the chemical similarity of their co-crystallized ligands with sorafenib and were retrieved from the PDB server. Selected proteins were prepared by adding hydrogens, adjusting protonation states of amino-acids and fixing missing side-chain atoms

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