Ninlaro (ixazomib)

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...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.

P1, N=24, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P=N/A, N=72, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

P2, N=30, Completed, Fred Hutchinson Cancer Center | Active, not recruiting --> Completed

P4, N=100, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University | Trial completion date: Jul 2025 --> Jul 2028 | Trial primary completion date: Jun 2024 --> Jun 2026

P2, N=79, Active, not recruiting, Alliance Foundation Trials, LLC. | Trial completion date: Jul 2026 --> Jun 2027 | Trial primary completion date: Oct 2025 --> Dec 2026

P2, N=112, Completed, University of Leeds | Unknown status --> Completed | Trial completion date: Jan 2021 --> Jan 2025

The IRd regimen demonstrates enhanced clinical efficacy in RRMM management, maintaining a safety profile comparable to the conventional Rd regimen. Furthermore, it effectively improves bone metabolism, reduces serum inflammation, and modulates serum biochemical parameters. Elevated M-protein expression correlates with poorer treatment outcome in RRMM.

To mimic ChaC1 overexpression by inducing endogenous ChaC1 high expression, a complementary ChaC1-induction-based screening was performed and revealed proteasome inhibitors (e.g., bortezomib, ixazomib, delanzomib) as potent inducers of endogenous ChaC1 via ATF4-dependent transcriptional activation. This functional convergence demonstrates that ChaC1 activation, either achieved through genetic manipulation or pharmacological induction, creates a synthetic lethal context for AUR in HCC cells. Together, our study establishes a ChaC1-based pharmacological discovery platform that identifies proteasome inhibitor and auranofin combination as a mechanistically rational anti-HCC strategy, providing both methodological innovation in drug repurposing screening and immediate translational potential for HCC treatment.

P1, N=24, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Rencofilstat increased extracellular secretion of cyclophilin B, but rencofilstat + ixazomib reduced glycosylation and, likely, the biological function of CD147 (CypB receptor) and decreased downstream ERK signaling. Rencofilstat + ixazomib may be a new strategy for increasing proteotoxic stress and apoptotic cell death in advanced prostate cancer cells with less toxic side effects.

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2025 --> Oct 2027 | Trial primary completion date: Oct 2025 --> Oct 2027