Phase II Clinical Trial of Mezigdomide/Carfilzomib/Dexamethasone (MeziKD) in Patients With Relapsed or Refractory Multiple Myeloma (MM) With Extramedullary Disease (EMD)

This phase II trial studies how well mezigdomide/carfilzomib/dexamethasone (MeziKD) works in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and have tumors from myeloma cells outside the bone marrow in the soft tissues or organs of the body (extramedullary disease [EMD]). Mezigdomide blocks important processes in myeloma cells and may lead to modulation of the immune system, including activation of T-lymphocytes, and downregulation of the activity of other proteins, some of which play key roles in the proliferation of certain cancer cell types. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Dexamethasone is a type of corticosteroid and is used to kill myeloma cells. It is used with other drugs to treat multiple myeloma. Giving MeziKD may kill more cancer cells in patients with relapsed/refractory multiple myeloma (RRMM) with EMD.

Start Date01 Nov 2024

Sponsor / Collaborator

Roswell Park Comprehensive Cancer Center

100 Clinical Results associated with Ubiquitin-protein ligases x CRBN

100 Translational Medicine associated with Ubiquitin-protein ligases x CRBN

0 Patents (Medical) associated with Ubiquitin-protein ligases x CRBN

Literatures (Medical) associated with Ubiquitin-protein ligases x CRBN

01 Sep 2024·Nature Chemical Biology

Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates

Article

Author: Fischer, Eric S ; Tsai, Ryan W ; Chen, James ; Donovan, Katherine A ; Huang, Hai-Tsang ; Xiong, Yuan ; Su, Shuyao ; Zhao, Xu ; Mageed, Nada ; Lumpkin, Ryan J ; Sellers, William R

Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.

01 Apr 2024·Cell Chemical Biology

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication

Article

Author: Reitz, Allen B ; Shu, Sherry T ; Tice, Colin M ; Shi, Haibin ; Emert-Sedlak, Lori A ; Smithgall, Thomas E ; Alvarado, John J

The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the cereblon E3 ubiquitin ligase thalidomide-binding domain in vitro and triggered Nef degradation in a T cell expression system. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.

01 Mar 2024·Journal of Biological Chemistry

Monoubiquitination empowers ubiquitin chain elongation

Article

Author: Wu, Kenneth ; Pan, Zhen-Qiang ; DeVita, Robert J

Ubiquitination often generates lysine 48-linked polyubiquitin chains that signal proteolytic destruction of the protein target. A significant subset of ubiquitination proceeds by a priming/extending mechanism, in which a substrate is first monoubiquitinated with a priming E2-conjugating enzyme or a set of E3 ARIH/E2 enzymes specific for priming. This is then followed by ubiquitin (Ub) chain extension catalyzed by an E2 enzyme capable of elongation. This report provides further insights into the priming/extending mechanism. We employed reconstituted ubiquitination systems of substrates CK1α (casein kinase 1α) and β-catenin by Cullin-RING E3 Ub ligases (CRLs) CRL4^CRBN and CRL1^βTrCP, respectively, in the presence of priming E2 UbcH5c and elongating E2 Cdc34b (cell division cycle 34b). We have established a new "apyrase chase" strategy that uncouples priming from chain elongation, which allows accurate measurement of the decay rates of the ubiquitinated substrate with a defined chain length. Our work has revealed highly robust turnover of monoubiquitinated β-catenin that empowers efficient polyubiquitination. The results of competition experiments suggest that the interactions between the ubiquitinated β-catenin and CRL1^βTrCP are highly dynamic. Moreover, ubiquitination of the Ub-modified β-catenin appeared more resistant to inhibition by competitors than the unmodified substrate, suggesting tighter binding with CRL1^βTrCP. These findings support a role for conjugated Ub in enhancing interactions with E3.

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