LDHA inhibitors(AstraZeneca/Univ Manchester)

There is compelling evidence that increased LDHA expression and lactate accumulation promote tumor progression, particularly in patients with basal/quasi-mesenchymal (QM) tumor subtypes that exhibit a glycolytic phenotype. Despite efforts to develop small-molecule inhibitors, no LDHA inhibitor is currently available in the clinic, and advancing new chemical space is needed. In our earlier studies, we identified hits, containing a novel hydroxy pyrimidinone motif, including ZINC2783354 and ZINC4978206, against LDHA. In this study, we performed pharmacokinetic evaluation and in vivo metabolic profiling of our starting hit to inform the design of new analogs, leading to the identification of pyrimidinedione as a new chemotype with LDHA inhibitory activity. The most promising compound, HP19, inhibited LDHA with IC₅₀ of 5.2 μM, demonstrated lactate inhibition, and reduced H3K18 lactylation. HP19 resulted in a drastic reduction in ATP levels and inhibited proliferation of PANC-1 cells with IC₅₀ of 22.7 μM. The antiproliferative effects of HP19 in PANC-1 cells were mediated by G1/S cell cycle arrest and induction of apoptosis.