Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia

dc.contributor.authorRamdas, Baskar
dc.contributor.authorDayal, Neetu
dc.contributor.authorPandey, Ruchi
dc.contributor.authorLarocque, Elizabeth
dc.contributor.authorKanumuri, Rahul
dc.contributor.authorPasupuleti, Santhosh Kumar
dc.contributor.authorLiu, Sheng
dc.contributor.authorKanellopoulou, Chrysi
dc.contributor.authorChu, Elizabeth Fei Yin
dc.contributor.authorMohallem, Rodrigo
dc.contributor.authorVirani, Saniya
dc.contributor.authorChopra, Gaurav
dc.contributor.authorAryal, Uma K.
dc.contributor.authorLapidus, Rena
dc.contributor.authorWan, Jun
dc.contributor.authorEmadi, Ashkan
dc.contributor.authorHaneline, Laura S.
dc.contributor.authorHoltsberg, Frederick W.
dc.contributor.authorAman, M. Javad
dc.contributor.authorSintim, Herman O.
dc.contributor.authorKapur, Reuben
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2024-08-23T10:10:20Z
dc.date.available2024-08-23T10:10:20Z
dc.date.issued2024-06-17
dc.description.abstractActivating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. 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.
dc.eprint.versionFinal published version
dc.identifier.citationRamdas B, Dayal N, Pandey R, et al. Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia. J Clin Invest. 2024;134(12):e169245. Published 2024 Jun 17. doi:10.1172/JCI169245
dc.identifier.urihttps://hdl.handle.net/1805/42901
dc.language.isoen_US
dc.publisherThe American Society for Clinical Investigation
dc.relation.isversionof10.1172/JCI169245
dc.relation.journalThe Journal of Clinical Investigation
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectHematology
dc.subjectStem cells
dc.subjectHematopoietic stem cells
dc.titleAlkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia
dc.typeArticle
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