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Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma.
Leukemia. 2018 10; 32(10):2224-2239.L

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+Show Affiliations

Department of Hematology, Second Affiliated Hospital of Soochow University, Suzhou City, China. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Arvinas, LLC, New Haven, CT, USA. Ideaya Biosciences, San Diego, CA, USA.Arvinas, LLC, New Haven, CT, USA.Arvinas, LLC, New Haven, CT, USA.Arvinas, LLC, New Haven, CT, USA.Deptartment of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA. Department of Chemistry, Yale University, New Haven, CT, USA. Department of Pharmacology, Yale University, New Haven, CT, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rorlowsk@mdanderson.org. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rorlowsk@mdanderson.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29581547

Citation

Zhang, Xiaohui, et al. "Protein Targeting Chimeric Molecules Specific for Bromodomain and Extra-terminal Motif Family Proteins Are Active Against Pre-clinical Models of Multiple Myeloma." Leukemia, vol. 32, no. 10, 2018, pp. 2224-2239.
Zhang X, Lee HC, Shirazi F, et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia. 2018;32(10):2224-2239.
Zhang, X., Lee, H. C., Shirazi, F., Baladandayuthapani, V., Lin, H., Kuiatse, I., Wang, H., Jones, R. J., Berkova, Z., Singh, R. K., Lu, J., Qian, Y., Raina, K., Coleman, K. G., Crews, C. M., Li, B., Wang, H., Hailemichael, Y., Thomas, S. K., ... Orlowski, R. Z. (2018). Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia, 32(10), 2224-2239. https://doi.org/10.1038/s41375-018-0044-x
Zhang X, et al. Protein Targeting Chimeric Molecules Specific for Bromodomain and Extra-terminal Motif Family Proteins Are Active Against Pre-clinical Models of Multiple Myeloma. Leukemia. 2018;32(10):2224-2239. PubMed PMID: 29581547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. AU - Zhang,Xiaohui, AU - Lee,Hans C, AU - Shirazi,Fazal, AU - Baladandayuthapani,Veerabhadran, AU - Lin,Heather, AU - Kuiatse,Isere, AU - Wang,Hua, AU - Jones,Richard J, AU - Berkova,Zuzana, AU - Singh,Ram Kumar, AU - Lu,Jing, AU - Qian,Yimin, AU - Raina,Kanak, AU - Coleman,Kevin G, AU - Crews,Craig M, AU - Li,Bingzong, AU - Wang,Huihan, AU - Hailemichael,Yared, AU - Thomas,Sheeba K, AU - Wang,Zhiqiang, AU - Davis,R Eric, AU - Orlowski,Robert Z, Y1 - 2018/03/27/ PY - 2017/03/03/received PY - 2018/01/02/accepted PY - 2017/12/03/revised PY - 2018/3/28/pubmed PY - 2019/6/14/medline PY - 2018/3/28/entrez SP - 2224 EP - 2239 JF - Leukemia JO - Leukemia VL - 32 IS - 10 N2 - 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. SN - 1476-5551 UR - https://www.unboundmedicine.com/medline/citation/29581547/Protein_targeting_chimeric_molecules_specific_for_bromodomain_and_extra_terminal_motif_family_proteins_are_active_against_pre_clinical_models_of_multiple_myeloma_ L2 - http://dx.doi.org/10.1038/s41375-018-0044-x DB - PRIME DP - Unbound Medicine ER -