- Browse by Author
Browsing by Author "Dayal, Neetu"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia(The American Society for Clinical Investigation, 2024-06-17) Ramdas, Baskar; Dayal, Neetu; Pandey, Ruchi; Larocque, Elizabeth; Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Liu, Sheng; Kanellopoulou, Chrysi; Chu, Elizabeth Fei Yin; Mohallem, Rodrigo; Virani, Saniya; Chopra, Gaurav; Aryal, Uma K.; Lapidus, Rena; Wan, Jun; Emadi, Ashkan; Haneline, Laura S.; Holtsberg, Frederick W.; Aman, M. Javad; Sintim, Herman O.; Kapur, Reuben; Pediatrics, School of MedicineActivating 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.Item Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer(Elsevier, 2024) Dilday, Tinslee; Abt, Melissa; Ramos-Solís, Nicole; Dayal, Neetu; Larocque, Elizabeth; Oblak, Adrian L.; Sintim, Herman O.; Yeh, Elizabeth S.; Pharmacology and Toxicology, School of MedicineHuman epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at serine (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both autophagy and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.