VTP-50469

Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. The combination of mezigdomide with the Menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving Menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.

We performed cell viability experiments on leukemia cell lines (MV4; 11, MOLM13, RS4; 11, THP1, SEM, KOPN8, NOMO1, HL60, ML2) with single, two and three drug combinations using a menin inhibitor (VTP50469), a DOT1L inhibitor (EPZ5676), and a CDK9 inhibitor (AZD4573). Based on our preclinical in vitro findings, the co-inhibition of menin-DOT1L or menin-CDK9 is a promising approach for the treatment of MLL-r leukemia. The varying responses of different MLL-r leukemia cell lines to drug combination treatment indicate that not all cases of MLL-r leukemia will respond uniformly to treatment combinations. Taken together, our data provide a strategy to determine optimal treatment combinations for personalized treatment of MLL-r leukemia.

Consistent with our screen results, the depletion of PRC1.1 components led to a markedly increase in IC50 values when treated with the Menin inhibitor VTP50469 in both human and murine KMT2A-rearranged cell models...This is consistent with recent data from phase I clinical trial of revumenib (SNDX-5613) and preclinical patient derived xenograft models, wherein the Menin inhibitor persistently inhibited key KMT2A targets, even in resistant samples...In summary, our study identifies the non-canonical PRC1.1 as a key epigenetic driver of Menin-MLL resistance through a KMT2A target gene-independent mechanism which involves aberrant activation of MYC. We have further provided evidence that AML cells with loss of PRC1.1 are hypersensitive to BCL-2 inhibitor Venetoclax, opening a new therapeutic avenue for tackling Menin-resistant AMLs driven by polycomb inactivation.

We evaluated the combination of RAS/MAPK pathway inhibition by the MEK1/2 inhibitor selumetinib with the Menin inhibitor VTP-50469 (SNDX-5613) in a genetically defined, poor prognostic subgroup of pediatric leukemia harboring KMT2A-r with RAS mutations. The findings in our preclinical study suggest a promising, readily translatable treatment for patients with KMT2A-racute leukemias harboring RAS mutations. Mechanistically, enhanced downregulation of both MYC signaling and the RAS/MAPK pathway with the combinatorial therapy is likely a strong contributor to the observed efficacy. MYC, Acute leukemia, KMT2A

In vitro treatment studies using three different menin inhibitors (MI-2-2 / MI-503 / VTP50469) to disrupt the transcriptional activity of the KMT2A-R complex resulted in the downregulation of DYRK1A at the RNA and the protein level...Supporting our hypothesis, combining DYRK1A inhibitors with the MEK inhibitor trametinib antagonistically rescued KMT2A-R ALL cell proliferation, indicating that ERK hyperactivation is the main driver of DYRK1A inhibitor mediated cell cycle arrest... Our results validate DYRK1A as an important molecule to regulate cell proliferation via inhibition of MYC and ERK. Targeting DYRK1A results in the accumulation of BIM, which renders the cells sensitive to BCL2 inhibition via venetoclax. While further in vivo studies are needed, we predict that combining DYRK1A inhibition with venetoclax may be a novel precision medicine strategy for the treatment of KMT2A-R ALL.

Lenalidomide, CC-220, and CC-92480 all synergized with VTP-50469 to inhibit proliferation. In two of these experiments CC-92480 was also compared to lenalidomide and increased survival by 23.4% (p < 0.0005) and 28.1% (p < 0.05). In summary, the preclinical activity of CC-92480 in MLL1 -r and NPM1c AML models, particularly in combination with Menin-MLL1 inhibition, supports translation of this compound or a similarly potent, Ikaros-degrading CELMoD into clinical trials for these molecular subtypes of AML.

Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion driven leukemia is sensitive to the Menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells...Gene expression analysis revealed that Menin-MLL1 inhibition simultaneously suppresses a pro-leukemogenic gene expression program, including downregulation of the HOXA cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that Menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.

Objective: Investigate anti-leukemic activities, potential synergism, and mechanisms of menin-MLL1 inhibitor SDNX-50469, an equipotent surrogate of the clinical compound SNDX-5613 and venetoclax combination in vivo in an NPM1c/ FLT3-ITD/TKD PDX model. Our study validated menin as a therapeutic target and demonstrated that its inhibition synergizes with venetoclax in NPM1/FLT3-mutated AML, which warrants clinical evaluation. Inhibition of FLT3 may further enhance menin and Bcl-2 co-targeting efficacy in NPM1- and FLT3-mutated AML.

Aims To investigate the anti-leukemic activity and potential synergism and mechanisms of the combination of the menin-MLL1 inhibitor SDNX-50469, an equipotent surrogate of the clinical compound SNDX-5613 and venetoclax in vivo in an NPM1c/FLT3-ITD/TKD patient-derived xenograft (PDX) model. Conclusion Our study further validated menin as a therapeutic target and demonstrated that its inhibition synergizes with venetoclax in NPM1/FLT3-mutated AML, which warrants further clinical evaluation. Inhibition of FLT3 may further enhance the therapeutic efficacy of menin and Bcl-2 co-targeting in NPM1 and FLT3 mutated AML.

Several acute myeloid leukemia genetic sub-types converge on high expression of HOX genes, critical for their self-renewal. A new orally bioavailable Menin-MLL inhibitor (VTP-50469) appears to promote their differentiation through direct effects on the HOX cofactor MEIS1, paving the way for clinical trials.

We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.