Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment

The success of arsenic in acute promyelocytic leukemia
(APL) treatment
is hardly transferred to non-APL cancers, mainly due to the low selectivity
and weak binding affinity of traditional arsenicals to oncoproteins
critical for cancer survival. We present herein the reinvention of
aliphatic trivalent arsenicals (As) as reversible covalent warheads
of As-based targeting inhibitors toward Bruton’s tyrosine kinase
(BTK). The effects of As warheads’ valency, thiol protection,
methylation, spacer length, and size on inhibitors’ activity
were studied. We found that, in contrast to the bulky and rigid aromatic
As warhead, the flexible aliphatic As warheads were well compatible
with the well-optimized guiding group to achieve nanomolar inhibition
against BTK. The optimized As inhibitors effectively blocked the BTK-mediated
oncogenic signaling pathway, leading to elevated antiproliferative
activities toward lymphoma cells and xenograft tumor. Our study provides
a promising strategy enabling rational design of new aliphatic arsenic-based
reversible covalent inhibitors toward non-APL cancer treatment.