Discovery of molecular glue degrader for treatment of IMiDs-resistant multiple myeloma based on GLUT-mediated tumor targeting strategy.

Based on the tumor Warburg effect and the strategy of GLUT-mediated drug transport, we have successfully discovered a promising molecular glue immunomodulatory drug (IMiD) candidate that exhibits excellent dual-targeting capability in tumor selective drug uptake, immunotherapy and combating lenalidomide (LEN) and pomalidomide (POM) resistance in multiple myeloma. The structure-activity relationship study culminated in the identification of the lena- and pomalidomide-glycoconjugates (1 and 20) with potent antitumor activity in cancer cells overexpressing GLUT1, especially in the highly resistant human multiple myeloma to LEN and POM. Compound 20 could completely counteract the resistance of MM.1S cells to LEN and POM with resistance indices were reduced by 100- and 550-fold, respectively. It also achieved 60.5% tumor growth inhibition (TGI) (vs. 26.9% for POM) in a MM.1S/POM drug-resistance xenograft model. Mechanistic studies demonstrated that 20 could GLUT1-dependently accumulate in tumor cells and exert antitumor effects as molecular glue by inducing IKZF1 and CK1α degradation.