CC-92480 (Mezigdomide) is a novel Cereblon (CRBN) E3 ligase modulator (CELMoD) that typically functions as a molecular glue, exhibiting enhanced anti-tumor and immunomodulatory activities[1, 2]. CC-92480 is orally bioavailable and is indicated for the treatment of relapsed and refractory multiple myeloma[3]. Compared to conventional immunomodulatory drugs (IMiDs, such as lenalidomide and pomalidomide), CC-92480 demonstrates a stronger binding affinity for CRBN[4].
In vitro, treatment of lenalidomide-resistant H929 R10-1 cells with CC-92480 (1-100nM) for 4h induced the complete degradation of Ikaros and Aiolos proteins[3].
In vivo, treatment with CC-92480 (10mg/kg) for 28 to 55 days significantly improved the median survival of mice across four distinct patient-derived xenograft (PDX) models of acute myeloid leukemia (AML)[5].
References:
[1] Fernandez Forner D F, Fernandez-Llamazares A I. American Chemical Society-258th National Meeting and Exposition. San Diego, California, USA-August 25-29, 2019[J]. Drugs of the Future, 2019, 44(9).
[2] Lopez-Girona A, Havens C G, Lu G, et al. CC-92480 is a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity against sensitive and resistant multiple myeloma cells[J]. Blood, 2019, 134: 1812.
[3] Hansen J D, Correa M, Nagy M A, et al. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma[J]. Journal of medicinal chemistry, 2020, 63(13): 6648-6676.
[4] Rajendran G. Investigation of the anticancer activity and mechanisms of zinc diethyldithiocarbamate in multiple myeloma[J]. 2023.
[5] Bourgeois W, Aubrey B J, Cutler J A, et al. Potent Ikaros degradation by the cereblon E3 ligase modulator CC-92480 is effective in combination with Menin-MLL1 inhibition in MLL1-rearranged and NPM1-mutant AML[J]. Blood, 2021, 138: 208.