PhD Dissertation Defense of Mr. Muhammad Mansha of Chemistry Department
Congratulation to Muhammad Mansha on the successful presentation of his Ph.D. Dissertation,
detail of his dissertation is given below:
Title: Design, Synthesis, and Evaluation of 1,3 diaryl pyrazoles as inhibitors of GGTase-1, a target for anti-cancer drugs
Date: 8th May 2017
Venue: Bld 4 room 125
Ras and Rho proteins, involve in the pathogenesis of more than half of all forms of cancer, undergo posttranslational modification with an isoprenyl lipid catalyzed by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). This posttranslational modification is termed as prenylation. The attached lipid is required for proper function of the modified protein, either as a mediator of membrane association, a determinant for specific protein-protein interactions, or both. Accordingly, inhibitors for both of these enzymes have been developed. However, farnesyltransferase inhibitors (FTIs) have not performed up to expectation in solid tumors and failed to respond in many types of cancer. When FTase is inhibited, the human oncogenic Ras isoform K-RasB is geranylgeranylated by protein GGTase-I. GGTase-I is the enzyme that catalyzes geranylgeranylation, which in turn is important to the function of the majority of Rho GTPases and several other regulatory proteins. Earlier studies have demonstrated that many of these proteins contribute to tumor development and metastasis. Thus to effectively block Ras processing, the development of selective inhibitors of GGTase-I (GGTIs) is required. In addition to their potential to suppress alternate prenylation of K-Ras and hence impact on K-Ras-dependent oncogenesis, GGTIs have been proposed as potential drugs for anti-angiogenic therapy and for inhibiting metastatic progression of cancers (via impact on proteins such as RhoA/C), inflammatory disorders and those of vascular system, and for hepatitis C.
In this study, a series of pyrazole-based GGTIs, structural analogs of GGTI-DU40, 2-16 have been synthesized and biologically evaluated for their GGTas-1 and farnesyltransferase (FTase) inhibition. The screening results revealed that 2 (IC50 = 2.4 µM) and 5 (IC50 = 3.1 µM) are potent inhibitors of GGTase-I, possessing higher inhibitory activity compared to the control compound 1 (GGTI-DU40, IC50 = 3.3 µM). The anti-proliferative efficacies against MDA-MB-231 cells line of target compounds demonstrated a significantly higher activity of 2 (IC50 = 7.6 µM) compared to 1 (IC50 = 23.0 µM). The efficiency of the target compounds was further validated by western blot analysis in MDA-MB-231 cell line, which revealed very high inhibitory cellular activity of 2 and 5, demonstrating their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 with the crystal structure of GGTase-I 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 H-bonding interactions and π-π contacts between 2 and the binding pocket of GGTase-I. Therefore, highly potent in vitro activity of 2 merits its extensive in vivo investigation.
Chemical structures of target compounds 2-16
Some event pictures below: