Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs DNA damage caused by topoisomerase II (TOP2) and confers resistance to TOP2-targeting cancer drugs.
• Inhibiting TDP2 is a potential strategy to sensitize cancer cells to TOP2 poisons.

Purpose of the Study:

• To validate and elucidate the structure of a previously identified TDP2 inhibitor hit, P10A10.
• To explore structure-activity relationships (SAR) of triazolopyrimidine and triazolopyridine scaffolds for TDP2 inhibition.
• To identify novel TDP2 inhibitors with potential therapeutic applications.

Main Methods:

• Resynthesis and structure elucidation of compound P10A10.
• Synthesis and biochemical evaluation of 47 analogues based on triazolopyrimidine and triazolopyridine scaffolds.
• Determination of IC50 values for TDP2 inhibition.
• Assessment of cell permeability and cytotoxicity of lead compounds.

Main Results:

• The correct structure of P10A10 was identified as the 5-phenyl triazolopyrimidine regioisomer 7a.
• Four derivatives (7a, 17a, 17e, and 17z) exhibited significant TDP2 inhibition (IC50 < 50 µM).
• Compound 17z demonstrated excellent cell permeability and no cytotoxicity.

Conclusions:

• The 5-phenyl triazolopyrimidine scaffold and its bioisosteric triazolopyridine analogues are promising for developing TDP2 inhibitors.
• Compound 17z is a potent TDP2 inhibitor with favorable pharmacokinetic properties, warranting further investigation for cancer therapy.