Evaluation of VTP‐50469, a menin‐MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium

Abstract

Background: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1.Procedure: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines.Results: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC 50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 M for EwS cell lines. Conclusions:In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models. K E Y W O R D SEwing sarcoma, pediatric oncology, xenograft 1 of 4 wileyonlinelibrary.com/journal/pbc https://doi.

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition

“…To assess whether these results were idiosyncratic of the cell line, library, or inhibitor used, we performed a genome-wide CRISPR screen in an independently derived MLL-AF9 mouse cell line using VTP-50469, a more potent, selective, and orally bioavailable Menin-MLL inhibitor (refs. (25,27,28)). sgRNAs targeting Utx , M//3 , and M//4 were also among the most significantly enriched candidate genes identified in this genome-wide screen ( Fig.…”

“…Owing to its pro-oncogenic roles in mixed lineage leukemia and other malignancies, small molecule inhibitors targeting the Menin-MLL1 and Menin-MLL2 proteinprotein interactions have shown great promise for intercepting and treating different types of cancers 19,[22][23][24][25][26][27] . Notably, three structurally different Menin-MLL inhibitors have recently entered clinical trials (NCT04065399, NCT04067336, NCT04811560) and at least one has been granted fast track designation by the FDA for treatment of relapsed/refractory acute leukemias [26][27][28] . Thus, an understanding of the molecular mechanisms of action of these drugs would facilitate the development of biomarkers to predict therapeutic response and resistance and lead to rational design of more effective combination treatments.…”

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling

“…To this end, we employed a potent and selective inhibitor of the Menin-MLL1 interaction, VTP50469, which has shown remarkable pre-clinical efficacy. 32 Pharmacologically, VTP50469 displaced Menin from the Menin-MLL1 complex and inhibited chromatin occupancy of MLL at select genes and transcriptional activation. 32 Coincidentally, Tyr323, where AA binds to Menin, is one of the key sites for VTP50469 interacting with Menin.…”

Menin–MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers

“…In order to address this question, pharmacological formulations, pharmacokinetic studies, and long-term toxicity in other species should be investigated in the following studies. More intriguingly, the type of thiophenpyrimidine inhibitors was also revealed to be effective in inhibiting the proliferation of solid tumors, including prostate cancer [ 5 , 29 ], liver cancer [ 6 ], breast cancer [ 27 ], lung cancer [ 23 ], and osteosarcoma [ 50 ]. However, the molecular mechanism of these menin/MLL1 small molecules inhibiting the proliferation of solid tumor cells is not clear, and it can be roughly understood that they have a synergistic effect with tumor chemotherapy drugs and may participate in the signaling pathway of chemotherapy drugs to inhibit tumors, which comprises speculation and needs to be further proven.…”