Researchers in Indiana, USA, have unveiled a new compound precisely targeted to treat drug resistant acute myeloid leukaemia (AML).
Developers say their new molecule “fits like a glove” into the active site of the mutant FLT3 protein that causes resistance. The compound HSN748 was designed at Purdue University, Indiana, to fit the three-dimensional atomic structure of the protein.
“Despite the widespread occurrence and clinical importance of FLT3 mutations in causing AML, treatment options tailored to this genetic anomaly are scarce. Our goal was to identify new and powerful inhibitors targeting the mutations, particularly those resistant to currently approved FDA options,” said Dr Baskar Ramdas from Indiana University School of Medicine, joint first author of the study.
So far, the drug has been tested on laboratory mice. The mice were implanted with drug resistant AML, derived from human patients. They all survived for 120 days after treatment, the researchers report in the Journal of Clinical Investigation.
Co-leader of the study Dr Reuben Kapur, of the Indiana School of Medicine, said: “Our preclinical study results have shown incredible promise, and we’re excited to keep the momentum going so AML patients can have more resilient options.”
The drug designer Professor Herman Sintim, of Purdue University, said: “The three-dimensional atomic structure guided the molecular design and synthesis of HSN748 so it fits perfectly into the active site of drug-resistant mutants of FLT3, like a hand fitting into a glove.
“The enzymatic activity of FLT3 is crucial for AML cancer cell survival, so filling in the active site with HSN748 kills the enzyme’s activity and also kills the cancer cells.”
Source:
Ramdas B, Dayal N, Pandey R, Larocque E, Kanumuri R, Pasupuleti SK, Liu S, Kanellopoulou C, Chu EFY, Mohallem R, Virani S, Chopra G, Aryal UK, Lapidus R, Wan J, Emadi A, Haneline LS, Holtsberg FW, Aman MJ, Sintim HO, Kapur R. (2024) “Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.” Journal of Clinical Investigation, 17 June 2024, doi: 10.1172/JCI169245.
Link: https://www.jci.org/articles/view/169245
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