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    6ms
    Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy. (PubMed, RSC Med Chem)
    RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Among three compounds (HSN748, HSND19, and HSN608) evaluated for B/KR(G810C) brain tumors, HSN748 exhibited significant intracranial tumor inhibition. PK analysis indicated that HSN748 has a brain/plasma partition coefficient (K p) of 0.4, demonstrating its capability to penetrate the central nervous system (CNS).
    Journal
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    RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6)
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    RET fusion • RET mutation • CCDC6-RET fusion • RET positive
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    Retevmo (selpercatinib) • Gavreto (pralsetinib) • HSN608
    over1year
    Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia. (PubMed, J Clin Invest)
    AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs...We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.
    Journal
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    FLT3 (Fms-related tyrosine kinase 3) • TET2 (Tet Methylcytosine Dioxygenase 2)
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    Xospata (gilteritinib) • Vanflyta (quizartinib) • crenolanib (ARO-002) • HSN608