dapolsertib (MEN1703)

Post-molecular dynamics simulation MM-GBSA analysis further confirmed these interactions, with binding free energies for FLT3: Kaempferol (-73.75 kcal/mol), Apigenin (-68.76 kcal/mol), Pacritinib (-51.27 kcal/mol); and for PIM1: Tricetin (-64.28 kcal/mol), Diosmetin (-52.2 kcal/mol), SEL24 (-53.38 kcal/mol). FLT3 and MPO were identified as specific diagnostic and prognostic biomarkers for AML. This comprehensive in-silico analysis revealed promising therapeutic compounds from E. prostrata targeting FLT3 and PIM1, along with novel biomarker potentials of FLT3 and MPO for improved AML diagnosis and prognosis, subject to further experimental validation.

P2, N=178, Recruiting, Ryvu Therapeutics SA | Not yet recruiting --> Recruiting

We also show that MEN1703 downregulates stromal cytokines that promote cytokine-mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment-mediated resistance to FLT3 inhibitors.

P2, N=178, Not yet recruiting, Ryvu Therapeutics SA

P1/2, N=73, Completed, Menarini Group | Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> May 2023 | Trial primary completion date: Sep 2022 --> May 2023

Our data suggest that PIMs support pro-tumoral and immunosuppressive phenotype of cHL-TAMs. Since PIM activity is required for RS cell survival and immune escape, these kinases are rational targets for therapy in cHL, suggesting the use of PIM inhibitors, such as MEN1703, as a possible therapeutic approach .

The higher efficacy of this combination in-vivo and compared to monotherapy could be related to a very potent concomitant inhibition of FLT3 and PIM kinases affecting upregulated FLT3 signaling pathway in-vivo as demonstrated by the reduction of phosphorylation of downstream effector proteins, such as pS6. Overall, these experiments have demonstrated the antitumor potential of concomitant inhibition of FLT3 and PIM kinases which could drive a novel therapeutic strategy in AML.

To assess role of PIMs in TAMs RS-M were treated with a dual pan-PIM/FLT3 inhibitor MEN1703 and subjected to transcriptional biochemical and immunophenotype analyses...This suppressive effect was alleviated in cocultures with the PIM inhibitor-treated RS-M.Our data suggest that PIMs support pro-tumoral and immunosuppressive phenotype of cHL-TAMs. Since PIM activity is required for RS cell survival and immune escape these kinases are rational targets for therapy in cHL.

SEL24/MEN1703 had a manageable safety profile and single-agent activity in adult patients with R/R IDHm AML and may be a feasible therapeutic option in this difficult-to-treat population.

SEL24/MEN1703 had a manageable safety profi le and single-agent activity in adult patients with R/R IDHm AML and may be a feasible therapeutic option in this diffi cult-to-treat population.