Rapid Two-StepMulticomponent Synthesis and Structure-degradationRelationships of Selective HDAC6 PROTAC Degraders

Abstract This work reports on the development of selective histone deacetylase 6 (HDAC6) degraders based on a peptoid scaffold. Structure-based design identified the isocyanide-derived cap region as suitable exit vector for linker attachment, enabling rapid generation of CRBN-recruiting PROTACs via the Ugi four-component reaction. A focused library of 12 degraders revealed a strong dependence of activity on linker composition, with octyl-linked compounds (9e–h) showing the strongest HDAC6 degradation with half-maximal degradation values of 17–36 nM in kinetic HDAC6 degradation assays. The lead compounds selectively degraded HDAC6 in MM.1S and MV4–11 cells without affecting class I HDACs and demonstrated clean proteomic profiles. Functionally, compounds 9e and 9f displayed submicromolar antiproliferative activity against FLT3-ITD-mutated acute myeloid leukemia cells and suppressed proinflammatory signaling in immune cells. Both effects were associated in part with residual class I HDAC inhibition. Overall, this study establishes an efficient multicomponent strategy for PROTAC synthesis and highlights key structure-degradation relationships.