TY - JOUR
T1 - Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma
AU - Barton, Blaire E.
AU - Collins, Matthew K.
AU - Chau, Cindy H.
AU - Choo-Wosoba, Hyoyoung
AU - Venzon, David J.
AU - Steinebach, Christian
AU - Garchitorena, Kathleen M.
AU - Shah, Bhruga
AU - Sarin, Eric L.
AU - Gütschow, Michael
AU - Figg, William D.
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
KW - angiogenesis
KW - cereblon
KW - immunomodulatory drugs
KW - multiple myeloma
KW - resistance
UR - http://www.scopus.com/inward/record.url?scp=85197935108&partnerID=8YFLogxK
U2 - 10.3390/biom14060725
DO - 10.3390/biom14060725
M3 - Article
AN - SCOPUS:85197935108
SN - 2218-273X
VL - 14
JO - Biomolecules
JF - Biomolecules
IS - 6
M1 - 725
ER -