Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma

• Published in: Biomolecules (Basel, Switzerland) Vol. 14; no. 6; p. 725
• Main Authors: Barton, Blaire E, Collins, Matthew K, Chau, Cindy H, Choo-Wosoba, Hyoyoung, Venzon, David J, Steinebach, Christian, Garchitorena, Kathleen M, Shah, Bhruga, Sarin, Eric L, Gütschow, Michael, Figg, William D
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.06.2024; MDPI
• Subjects: Angiogenesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bone marrow; Cancer; Cell growth; Cell Line, Tumor; cereblon; Drug development; Drug Evaluation, Preclinical; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug therapy; FDA approval; Health aspects; Hematology; Humans; Immunomodulation; immunomodulatory drugs; Inflammation; Laboratories; Lead compounds; Life sciences; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Proteins; resistance; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology; Transcription factors; Tumor necrosis factor-TNF; Veins & arteries; Germany; United States > US; cereblon; multiple myeloma; immunomodulatory drugs; angiogenesis; resistance
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14060725

Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.