Development of novel PROTAC Small-Molecule Degraders of MDM2 Protein and Peptidomimetic Inhibitors Targeting WDR5-MLL1 Protein-Protein Interaction

[摘要] The transcription factor p53 plays an important role in suppression of tumor development, as it is involved in several important regulation of cell process, such as activation of DNA repair, cell cycle arrest, apoptosis and senescence. About 50% of human cancers carry mutated or deleted TP53, the gene coding p53 protein, which renders p53 nonfunctional as a tumor suppressor. Even in cancer cells with wild-type TP53, the p53 functions are inhibited by several mechanisms. Human MDM2 protein is a primary, endogenous cellular inhibitor of the tumor suppressor p53 through a direct protein-protein interaction, which makes it an attractive target for cancer treatment. In the past 15 years, a number of potent, selective and efficacious MDM2 inhibitors have been developed and advanced into clinical trials for cancer treatment. Recently, targeting protein degradation using small molecules emerged as a novel strategy for drug development. Herein, we present our design, synthesis and evaluation of MDM2 degraders based on a proteolysis targeting chimera (PROTAC) strategy. One of our most promising compounds (LE-102) could effectively induce MDM2 degradation at a concentration as low as 1 nM within 0.5 hour in RS4;11 leukemia cells. LE-102 achieves an IC50 value of 2.3 nM in cell growth inhibition of RS4;11 with wild-type p53. It can also induce complete and durable tumor regression in vivo against RS4;11 xenograft tumors in mice and can significantly extend the survival time in the RS4;11 survival model. Mechanism studies have shown that LE-102 is a highly potent and efficacious MDM2 degrader. The development of MDM2 degraders is a novel efficient strategy targeting MDM2 for cancer therapy.Inducing MDM2 protein degradation by PROTACs has shown its promising potential in cancer treatment. While during our study, a class of compounds based on the core structure of our MDM2 inhibitor MI-1061, failed to induce degradation of their consensus target, they displayed pronounced cell proliferation inhibition effects in several cancer cell lines. The cell growth inhibition activity of LD-277, a compound in this class, is not related to MDM2 degradation and activation of p53 pathway but mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. These findings demonstrated that a small modification could convert a PROTAC to molecular glue with unexpected mechanisms and effects. Careful target validation and activity evaluation are required in the development of PROTACs and molecular glue. MLL1 is a histone H3 Lysine 4 methyltransferase, an important regulator of transcription and mediator of normal development and disease. Translocation of MLL1 has been found widely in infant ALL and AML. Persistent activation of HoxA9 and MEIS1 caused by MLL1 fusions is important for sustaining the leukemic phenotype. Although MLL1 fusion proteins are oncogenic, they require the maintenance of a wild-type allele for leukemogenesis. WDR5 is important for the HMT activity of the wild-type MLL1 complex. Therefore, inhibition of WDR5-MLL1 protein-protein interaction could be a valid approach for the treatment of MLL-rearranged leukemias. Herein, we report the design, synthesis and evaluation of macrocyclic peptidomimetics that bind to WDR5 and block the WDR5-MLL protein-protein interaction. LC-337 binds to WDR5 with a Ki value < < 1 nM, inhibits cell growth in MOLM13 with IC50 value of 33 nM and is >800 times better than the previously reported compound MM-401.

[发布机构] University of Michigan

[效力级别] Molecular glue

[关键词] MDM2 PROTAC;Molecular glue;WDR5 Inhibitor;Science (General);Science;Medicinal Chemistry