Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies

In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC₅₀ = 2.4 μM) and 5 (IC₅₀ = 3.1 μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC₅₀ = 3.3 μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231 cells which indicated a significantly higher activity of 2 (IC₅₀ = 7.6 μM) compared to 1 (IC₅₀ = 23.0 μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231 cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C = cysteine, aa = aliphatic amino acids, and X = any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in vivo investigation to further assess its efficacy and cytotoxicity.