Discovery of Novel SIK2/3 Inhibitors for the Potential Treatment of MEF2C+ Acute Myeloid Leukemia (AML)

The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds of pan-SIK or SIK2/3 inhibitors have been reported, few of them showed sufficient in vitro or in vivo antitumor activity. Based on the proposed binding mode of the hit molecule (7), chemical space in the solvent/P-loop region was explored via fragment growing/replacement, supported by the generative chemistry platform. Further SAR exploration and ADME optimization led to the discovery of 7s, which exhibited excellent potency and strong selectivity in MEF2C high-expression cell lines over MEF2C-low cell lines. Moreover, oral administration of 7s was found to demonstrate significant tumor growth inhibition in a MV4-11 AML mice CDX model without any body weight loss. This work highlights the potential of targeting MEF2C-dependent AML by selective oral SIK2/3 inhibitors, which was supported by the generative models.