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Exploiting PKM2-PARP1 dependency: Isoselenazolium-olaparib conjugates achieve multimodal PKM2 suppression
Pavels Dimitrijevs1, Marina Makrecka-Kuka1, Diana Zelencova-Gopejenko1
1Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006, Riga, Latvia.
Abstract:
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.
Insights
New dual inhibitors targeting Pyruvate Kinase M2 (PKM2) and PARP1 were developed. These conjugates block PKM2’s nuclear function and inhibit cancer cell proliferation, offering a novel therapeutic strategy.
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.
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