First-in-Class Potent, Dual HDAC6/Proteasome Inhibitors Lacking a Hydroxamic Acid Motif: Discovery of Novel Anti-Multiple Myeloma Agents

Alexandria M Chan; Brandon D Lowe; Andrea L Cottingham; Daniel Van Eker; Asaminew H Aytenfisu; Jace W Jones; Alexander D MacKerell Jr; Ryan M Pearson; Steven Fletcher

doi:10.1021/acsmedchemlett.5c00500

First-in-Class Potent, Dual HDAC6/Proteasome Inhibitors Lacking a Hydroxamic Acid Motif: Discovery of Novel Anti-Multiple Myeloma Agents

ACS Med Chem Lett. 2025 Dec 22;17(1):125-132. doi: 10.1021/acsmedchemlett.5c00500. eCollection 2026 Jan 8.

Authors

Alexandria M Chan¹, Brandon D Lowe¹, Andrea L Cottingham¹, Daniel Van Eker¹, Asaminew H Aytenfisu^{1

2}, Jace W Jones¹, Alexander D MacKerell Jr^{1

2

3}, Ryan M Pearson^{1

3}, Steven Fletcher^{1

3}

Affiliations

¹ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, Maryland 21201, United States.
² Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Penn St., Baltimore, Maryland 21201, United States.
³ University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Baltimore, Maryland 21201, United States.

PMID: 41531963
PMCID: PMC12794061 (available on 2027-01-08)
DOI: 10.1021/acsmedchemlett.5c00500

Abstract

Motivated by promising clinical trial data for the combination of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat with the proteasome inhibitor bortezomib in relapsed/refractory multiple myeloma (MM) patients, we engineered dual HDAC6/proteasome inhibitors. FDA-approved HDAC inhibitors suffer from off-target effects, which have been attributed, in part, to their lack of HDAC isoform selectivity. Furthermore, they are potentially mutagenic, because of their indispensable hydroxamic acid zinc-binding groups (ZBGs). Deploying the HDAC6-selective phenyl-4-hydroxamic acid motif, and O-carbamoylated hydroxamates as hydroxamic acid surrogates, then grafting to the electrophilic boronic acid warhead of bortezomib/ixazomib, we discovered several dual HDAC6/proteasome inhibitors that were potent in cell-free assays, inhibiting the chymotrypsin-like (CL) proteasomal activity on par with that of bortezomib, and many compounds demonstrated selectivity for HDAC6 over HDAC1 as predicted. Moreover, several dual HDAC6/proteasome inhibitors were submicromolar inhibitors of MM cell growth. Of particular interest, AMC-3-030 with an O-(N-phenylcarbamoyl)-hydroxamate ZBG emerged as an exciting lead for further studies.

Keywords: Cancer; HDAC6; bortezomib; multiple myeloma; polypharmacology; proteasome.