Exploiting PKM2-PARP1 dependency: Isoselenazolium-olaparib conjugates achieve multimodal PKM2 suppression

Pyruvate Kinase M2 (PKM2) is a central regulator of glucose metabolism in cancer cells whose function extends beyond glycolysis. PKM2 can translocate to the nucleus, where it acts as an oncogenic transcription factor. In turn, its nuclear retention is enhanced upon binding with poly(ADP-ribose), which is prevented by PARP1 inhibition. To exploit this interplay, a new class of PKM2-PARP1 inhibitor conjugates was designed and synthesized. The lead compound 9f potently inhibited PKM2 and PARP1 (IC₅₀ = 261 ± 23 nM and 39.5 ± 3.1 nM, respectively). 9f also reduced PKM2 dimerization, lowered nuclear accumulation, and selectively downregulated PKM2 mRNA. Functionally, 9f demonstrated broad antiproliferative activity across multiple cancer cell lines (IC₅₀ = 2.9-6.6 μM) and completely inhibited 3D cancer cell spheroid formation at 12.5 μM. These findings establish PKM2-PARP1 conjugates as a novel class of dual inhibitors that impair PKM2 at enzymatic, nuclear, and transcriptional levels, extending PARP inhibition strategies beyond their established role in DNA-repair pathways.