AS104

AS104 is a small molecule inhibitor of **adenylosuccinate synthetase 2 (ADSS2)**, an enzyme that catalyzes the first committed and rate-limiting step of adenosine monophosphate (AMP) biosynthesis from inosine monophosphate (IMP). Discovered via a fragment-based virtual screen of approximately 8 million compounds, AS104 binds directly to ADSS2 and inhibits its catalytic activity with an IC50 of 2.43 µM. In preclinical models of **acute myeloid leukemia (AML)**, AS104 treatment results in AMP depletion and the repression of AMPK activity, which increases the vulnerability of AML cells to mitochondrial apoptosis. This mechanism sensitizes both AML cell lines and primary venetoclax-resistant samples to BH3 mimetics, such as venetoclax and MCL1 inhibitors, potentially offering a strategy to overcome treatment resistance in AML patients.