Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L

Chavarria, Gustavo E.; Horsman, Michael R.; Arispe, Wara M.; Kumar, G. Suresh; Chen, Shen-En; Strecker, Tracy E.; Parker, Erica N.; Chaplin, David J.; Pinney, Kevin G.; Trawick, Mary Lynn

doi:10.1016/j.ejmech.2012.10.039

Cited by 29 publications

(15 citation statements)

References 22 publications

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“…Kinetic analysis of the closely related thiosemicarbazone analogue X (Figure 3) showed that it was a time-dependent and slowly reversible inhibitor of cathepsin L. 47 The reaction progress curves for benzoylbenzophenone thiosemicarbazone analogues 1 and 32 (Figure 5) were comparable to those previously observed for (3-bromo-3'-hydroxybenzophenone) thiosemicarbazone X . The cathepsin L catalyzed reaction was carried out with N-carbobenzyloxy-L-Phe-L-Arg-7-amino-4-methylcoumarin (Z-FR-AMC) as substrate in the presence of varying concentrations (0–10 μM) of thiosemicarbazone analogues 1 and 32 .…”

Section: Resultssupporting

confidence: 67%

“…A number of different binding modes with similar interaction energies were obtained from docking analogues 1 and 32 . In each case, several of the top binding orientations placed the thiocarbonyl carbon atom of the inhibitor in close proximity to the Cys25 thiolate in a similar manner to that observed with benzophenone thiosemicarbazones X 47 and XI . 45 One of the top binding orientations for each of benzoylbenzophenone thiosemicarbazone analogues 1 and 32 which positions the Cys25 thiolate within 5 Å of the thiocarbonyl carbon atom is illustrated in Figure 6.…”

Section: Resultsmentioning

confidence: 67%

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Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

Parker

Song

Kumar

et al. 2015

Bioorganic & Medicinal Chemistry

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Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 μM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 μM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 67%

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

Parker

Song

Kumar

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Conversely, tumor progression studies in CTSL −/− mice revealed that CTSL deficiency significantly hampered the progression of benign encapsulated pancreatic tumors into highly invasive carcinomas [21]. Further, our previous findings have reported that pharmacological inhibition of CTSL using 3-bromophenyl-3-hydroxyphenyl-ketone thiosemicarbazone (KGP94) significantly impairs the invasive and metastatic capacities of human breast and prostate cancer cells [22–24]. While these studies are clearly indicative of the importance of CTSL in metastatic progression, they shed little light on the involvement of CTSL in the angiogenic process.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

Sudhan

Rabaglino

Wood

et al. 2016

Clin Exp Metastasis

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A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micrometastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesis in vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients.

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“…Despite the continuous efforts in the direction of finding novel cathepsin L inhibitors, there are no clinical agents available in human clinical trials yet [31]. This study establishes the use of thiosemicarbazone derivatives by contributing towards understanding its essential characteristics as potent anti-cancer candidate and thus paves way for an accelerated evaluation of novel thiosemicarbazone-based lead candidates using the predicted QSAR model.…”

Section: Introductionmentioning

confidence: 89%

“…Benzophenone thiosemicarbazone derivatives have earlier been reported as potential therapeutics against malaria, sleeping sickness and chagas' disease [27-30]. Recently, antitumor activity of KGP94, a functionalized benzophenone thiosemicarbazone derivative, was evaluated for breast cancer against cathepsin L [31]. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) has already been evaluated as ribonucleotide reductase inhibitor for anticancer therapy [32].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into mode of action of novel natural cathepsin L inhibitors

et al. 2013

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BackgroundDevelopment of a cancerous cell takes place when it ceases to respond to growth-inhibiting signals and multiplies uncontrollably and can detach and move to other parts of the body; the process called as metastasis. A particular set of cysteine proteases are very active during cancer metastasis, Cathepsins being one of them. They are involved in tumor growth and malignancy and have also been reported to be overexpressed in tumor cell lines. In the present study, a combinatorial approach comprising three-dimensional quantitative structure-activity relationship (3D QSAR), ligand-based pharmacophore modelling and search followed by cathepsin L structure-based high throughput screening was carried out using an initial set of 28 congeneric thiosemicarbazone derivatives as cathepsin L inhibitors. A 3D QSAR was derived using the alignment of a common thiosemicarbazone substructure. Essential structural features responsible for biological activity were taken into account for development of a pharmacophore model based on 29 congeneric thiosemicarbazone derivatives. This model was used to carry out an exhaustive search on a large dataset of natural compounds. A further cathepsin L structure-based screen identified two top scoring compounds as potent anti-cancer leads.ResultsThe generated 3D QSAR model showed statistically significant results with an r2 value of 0.8267, cross-validated correlation coefficient q2 of 0.7232, and a pred_r2 (r2 value for test set) of 0.7460. Apart from these, a high F test value of 30.2078 suggested low probability of the model's failure. The pharmacophoric hypothesis chosen for searching the natural compound libraries was identified as DDHRR, where two Ds denote 2 hydrogen donors, H represents a hydrophobic group and two Rs represent aromatic rings, all of which are essential for the biological activity. We report two potential drug leads ZINC08764437 (NFP) and ZINC03846634 (APQ) obtained after a combined approach of pharmacophore-based search and structure-based virtual screen. These two compounds displayed extra precision docking scores of -7.972908 and -7.575686 respectively suggesting considerable binding affinity for cathepsin L. High activity values of 5.72 and 5.75 predicted using the 3D QSAR model further substantiated the inhibitory potential of these identified leads.ConclusionThe present study attempts to correlate the structural features of thiosemicarbazone group with their biological activity by development of a robust 3D QSAR model. Being statistically valid, this model provides near accurate values of the activities predicted for the congeneric set on which it is based. These predicted activities are good for the test set compounds making it indeed a statistically sound 3D QSAR model. The identified pharmacophore model DDHRR.8 comprised of all the essential features required to interact with the catalytic triad of cathepsin L. A search for natural compounds based on this pharmacophore followed by docking studies further screened out two top scoring candidates: NFP and ...

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Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L

Cited by 29 publications

References 22 publications

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

Mechanistic insights into mode of action of novel natural cathepsin L inhibitors

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