Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design—Part 2

McBride, Christopher M.; Cheruvallath, Zacharia S.; Komandla, Mallareddy; Tang, Mingnam; Farrell, Pamela; Lawson, J. David; Vanderpool, Darin; Wu, Yun; Dougan, D.R.; Płonowski, Artur; Holub, Corine; Larson, Christopher J.

doi:10.1016/j.bmcl.2016.04.072

Cited by 22 publications

(31 citation statements)

References 2 publications

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“…Recently, using the fragment-based drug discovery approach (FBDD), a 6-substituted indazole core was identified as an orally efficacious potent reversible MetAP2 inhibitor[69]. Based on those findings, a pyrazolo[4,3-b]indole core was designed using the structure-based drug discovery (SBDD) approach[70]. One pharmacokinetically acceptable compound was further evaluated in a DIO-mouse model for obesity and a 4% reduction in body weight was observed.…”

Section: Reversible Vs Irreversible Methionine Aminopeptidase Inhibitorsmentioning

confidence: 99%

“…One pharmacokinetically acceptable compound was further evaluated in a DIO-mouse model for obesity and a 4% reduction in body weight was observed. In addition, this compound was high specific based on the data evaluated in a Ricerca Comprehensive Pharmacological Profile panel including 100 biological targets and a panel of proteases[69,70]. These findings showed great promise of developing potent reversible MetAP2 inhibitors for obesity and hopefully for anti-cancer drugs in the foreseeable future.…”

Section: Reversible Vs Irreversible Methionine Aminopeptidase Inhibitorsmentioning

confidence: 99%

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Common therapeutic target for both cancer and obesity

Chang

2017

WJBC

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Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishable through the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase (MetAP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible MetAP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins.

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Section: Reversible Vs Irreversible Methionine Aminopeptidase Inhibitorsmentioning

confidence: 99%

Section: Reversible Vs Irreversible Methionine Aminopeptidase Inhibitorsmentioning

confidence: 99%

Common therapeutic target for both cancer and obesity

Chang

2017

WJBC

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“…We used a diverse set of MetAP2 inhibitors to evaluate the specific effects of MetAP2 inhibition, irrespective of chemical class. We selected two compounds that had been previously characterized, beloranib and A357300, as well as a compound from our distinct pyrazolo-indole chemical series (McBride et al, 2016). Figure 1 shows the chemical structure of each of these inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Reagents. Small-molecule compounds were synthesized at Takeda California, San Diego, CA, as described in Cheruvallath et al, (2016) and McBride et al, (2016). For in vitro studies, compounds were solvated in dimethyl sulfoxide (DMSO) and for in vivo studies compound 1 was formulated in 0.5% methylcellulose; beloranib was formulated in 2% captisol/0.3% citric acid, and A357300 was formulated in 0.2% hydroxypropylmethyl cellulose.…”

Section: Methodsmentioning

confidence: 99%

Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors

Farrell

Zopf

Huang

et al. 2019

J Pharmacol Exp Ther

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Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans. However, there is a need to develop efficacious compounds that specifically inhibit MetAP2 with an improved safety profile. The objective of this study was to identify a PD biomarker for selecting potent, efficacious compounds and for predicting clinical efficacy that would result from inhibition of MetAP2. Here we report the use of NMet14-3-3g for this purpose. Treatment of primary human cells with MetAP2 inhibitors resulted in an approx. 10-fold increase in NMet14-3-3g levels. Furthermore, treatment of diet-induced obese mice with these compounds reduced body weight (approx. 20%) and increased NMet14-3-3g (approx. 15-fold) in adipose tissues. The effects on target engagement and body weight increased over time and were dependent on dose and administration frequency of compound. The relationship between compound concentration in plasma, NMet14-3-3g in tissue, and reduction of body weight in obese mice was used to generate a pharmacokineticpharmacodynamic-efficacy model for predicting efficacy of MetAP2 inhibitors in mice. We also developed a model for predicting weight loss in humans using a target engagement PD assay that measures inhibitor-bound MetAP2 in blood. In summary, MetAP2 target engagement biomarkers can be used to select efficacious compounds and predict weight loss in humans. SIGNIFICANCE STATEMENT The application of target engagement pharmacodynamic biomarkers during drug development provides a means to determine the dose required to fully engage the intended target and an approach to connect the drug target to physiological effects. This work exemplifies the process of using target engagement biomarkers during preclinical research to select new drug candidates and predict clinical efficacy. We determine concentration of MetAP2 antiobesity compounds needed to produce pharmacological activity in primary human cells and in target tissues from an appropriate animal model and establish key relationships between pharmacokinetics, pharmacodynamics, and efficacy, including the duration of effects after drug administration. The biomarkers described here can aid decision-making in early clinical trials of MetAP2 inhibitors for the treatment of obesity.

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“…Moreover, there are tens of reversible inhibitors of both natural and synthetic origin. They include anthranilic acid sulfonamides [ 88 ], bengamides [ 89 ], benzoselnazalones [ 63 ] and compounds based on bestatin [ 90 ], 1,2,4-triazole [ 91 ], and pyrazolo[4,3-b]indole [ 92 ]. Research on new, reversible agents that are safe for organisms is ongoing.…”

Section: Perspective and Conclusionmentioning

confidence: 99%

Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

et al. 2018

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The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X2 are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound (Ki in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D's action on tumors and suggests new avenues and molecules for medical applications.

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Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design—Part 2

Cited by 22 publications

References 2 publications

Common therapeutic target for both cancer and obesity

Common therapeutic target for both cancer and obesity

Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors

Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

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