Design, synthesis and biological evaluation of 3-amino-6-(2-hydroxyphenyl)pyridazin-4-aryl derivatives as SMARCA2/4 degraders.

SMARCA2/4, a pair of mutually exclusive core catalytic subunits of the chromatin remodeling complex SWI/SNF, play essential roles in regulating gene transcription. Given the pivotal role of SMARCA2/4 in sustaining the oncogenic transcription program and promoting proliferation in acute myeloid leukemia (AML), the development of non-selective degraders holds practical therapeutic implications. Herein, we designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) by conjugating the VHL ligand to a SMARCA2/4 bromodomain ligand, 2-(6-amino-5-phenylpyridazin-3-yl)phenol, using various linkers. Preliminary evaluations identified A11 as the most potent molecule that efficiently degraded SMRACA2 (DC50 = 3.0 nM, Dmax = 98 %) and SMARCA4 (DC50 = 4.0 nM, Dmax = 98 %). A11 significantly inhibited the proliferation of hematological cancer cell lines, including MV-4-11, MOLM-13 and SU-DHL-4. It decreased the levels of SMARCA2/4 through the ubiquitin-proteasome system. Global proteome analysis revealed that A11 was able to selectively target and degrade SMARCA2/4. Additionally, A11 caused cell cycle arrest at the G0/G1 phase and induced cell apoptosis in MV-4-11 and MOLM-13 cells. It also blocked the oncogenic activity of MYC and other disease-related genes in AML cells. Overall, our data clarified that A11 is a promising SMARCA2/4 degrader for cancer therapy, which is worthy of further evaluation.