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

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Pyruvate Kinase M2 (PKM2) regulates glucose metabolism and acts as an oncogenic transcription factor in the nucleus.
• Nuclear retention of PKM2 is stabilized by poly(ADP-ribose) (PAR) binding, a process inhibited by PARP1 inhibitors.
• Targeting PKM2's nuclear function presents a novel strategy in cancer therapy.

Purpose of the Study:

• To design and synthesize novel PKM2-PARP1 inhibitor conjugates.
• To evaluate the inhibitory potential and functional effects of these conjugates on cancer cells.
• To explore a new therapeutic approach by dual inhibition of PKM2 and PARP1.

Main Methods:

• Synthesis of PKM2-PARP1 inhibitor conjugates, with compound 9f as the lead.
• Biochemical assays to determine IC50 values for PKM2 and PARP1 inhibition.
• Assessment of effects on PKM2 dimerization, nuclear translocation, and mRNA levels.
• Evaluation of antiproliferative activity and 3D spheroid formation inhibition in cancer cell lines.

Main Results:

• The lead compound 9f potently inhibited both PKM2 (IC50 = 261 ± 23 nM) and PARP1 (IC50 = 39.5 ± 3.1 nM).
• Compound 9f reduced PKM2 dimerization, decreased its nuclear accumulation, and selectively downregulated PKM2 mRNA.
• 9f exhibited broad antiproliferative effects (IC50 = 2.9-6.6 μM) and completely inhibited 3D cancer cell spheroid formation.

Conclusions:

• PKM2-PARP1 conjugates represent a novel class of dual inhibitors.
• These conjugates effectively impair PKM2 at enzymatic, nuclear, and transcriptional levels.
• This strategy extends PARP inhibition beyond DNA repair, offering new avenues for cancer treatment.