Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma.

Abstract

Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0/G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis. These agents specifically decreased cellular levels of downstream BRD4 targets, including c-MYC and N-MYC, and a Cereblon-targeting PROTAC showed downstream effects similar to those of an immunomodulatory agent. Notably, PROTACs overcame bortezomib, dexamethasone, lenalidomide, and pomalidomide resistance, and their activity was maintained in otherwise isogenic myeloma cells with wild-type or deleted TP53. Combination studies showed synergistic interactions with dexamethasone, BH3 mimetics, and Akt pathway inhibitors. BET-specific PROTACs induced a rapid loss of viability of primary cells from myeloma patients, and delayed growth of MM1.S-based xenografts. Our data demonstrate that BET degraders have promising activity against pre-clinical models of multiple myeloma, and support their translation to the clinic for patients with relapsed and/or refractory disease.

• Authors: Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
• Journal: Leukemia (Leukemia) Vol. 32 Issue 10 Pg. 2224-2239 (10 2018) ISSN: 1476-5551 [Electronic] England
• PMID: 29581547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Nuclear Proteins
• Proteins
• Proto-Oncogene Proteins c-myc
• Tumor Suppressor Protein p53
• bromodomain and extra-terminal domain protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Amino Acid Motifs (drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Multiple Myeloma (drug therapy, metabolism)
• Nuclear Proteins (metabolism)
• Protein Domains (drug effects)
• Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination (drug effects)
• Xenograft Model Antitumor Assays