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Yan Li, Leonidas N Carayannopoulos, Michael Thomas, Maria Palmisano, Simon Zhou
CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals...
2016: Clinical Pharmacology: Advances and Applications
Rosalba Camicia, Hans C Winkler, Paul O Hassa
Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options.Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype...
2015: Molecular Cancer
Jan Krönke, Emma C Fink, Paul W Hollenbach, Kyle J MacBeth, Slater N Hurst, Namrata D Udeshi, Philip P Chamberlain, D R Mani, Hon Wah Man, Anita K Gandhi, Tanya Svinkina, Rebekka K Schneider, Marie McConkey, Marcus Järås, Elizabeth Griffiths, Meir Wetzler, Lars Bullinger, Brian E Cathers, Steven A Carr, Rajesh Chopra, Benjamin L Ebert
Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS...
July 9, 2015: Nature
Patrick R Hagner, Hon-Wah Man, Celia Fontanillo, Maria Wang, Suzana Couto, Mike Breider, Chad Bjorklund, Courtney G Havens, Gang Lu, Emily Rychak, Heather Raymon, Rama Krishna Narla, Leo Barnes, Gody Khambatta, Hsiling Chiu, Jolanta Kosek, Jian Kang, Michael D Amantangelo, Michelle Waldman, Antonia Lopez-Girona, Ti Cai, Michael Pourdehnad, Matthew Trotter, Thomas O Daniel, Peter H Schafer, Anke Klippel, Anjan Thakurta, Rajesh Chopra, Anita K Gandhi
Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects...
August 6, 2015: Blood
Vincent Jacques, Anthony W Czarnik, Thomas M Judge, Lex H T Van der Ploeg, Sheila H DeWitt
Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety...
March 24, 2015: Proceedings of the National Academy of Sciences of the United States of America
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