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.
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia; Center of Research Excellence in Nanotechnology, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
Muhammad
M
Mansha
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate School, 8 College Road, Singapore 169857, Singapore.
Udayappan Udhaya
UU
Kumari
Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527 Athens, Greece.
Zoe
Z
Cournia
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia. Electronic address: nullah@kfupm.edu.sa.
Nisar
N
Ullah
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C530102:GGTI-DU40; D011720:Pyrazoles; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase
Cancer therapy; Cell proliferation; Docking; GGT1 inhibitor; Rap1A