Current anti-diabetic agents and their molecular targets: A review.

// Samaher Besbes 1,2 , Massoud Mirshahi 1,2 , Marc Pocard 1,2 and Christian Billard 1,2 1 INSERM U 965, Hopital Lariboisiere, Paris, France 2 Universite Paris Diderot, UMR S965, Paris, France Correspondence to: Christian Billard, email: // Keywords : anticancer therapy; apoptosis; targeting BCL-2 family proteins; BH3 mimetics; prosurvival protein antagonists Received : February 12, 2015 Accepted : April 01, 2015 Published : April 19, 2015 Abstract Proteins of the BCL-2 family control the mitochondrial pathway of apoptosis. Targeting these proteins proves to be an attractive strategy for anticancer therapy. The biological context is based on the fact that BH3-only members of the family are specific antagonists of prosurvival members. This prompted the identification of “BH3 mimetic” compounds. These small peptides or organic molecules indeed mimic the BH3 domain of BH3-only proteins: by selectively binding and antagonizing prosurvival proteins, they can induce apoptosis in malignant cells. Some small-molecule inhibitors of prosurvival proteins have already entered clinical trials in cancer patients and two of them have shown significant therapeutic effects. The latest developments in the field of targeting BCL-2 family proteins highlight several new antagonists of prosurvival proteins as well as direct activators of proapoptotic proteins. These compounds open up novel prospects for the development of BH3 mimetic anticancer drugs.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=3868&path%5B%5D=8359

New dimension in therapeutic targeting of BCL-2 family proteins

Protein–protein interactions (PPIs) are carrying out diverse functions in living systems and are playing a major role in the health and disease states. Low molecular weight (LMW) “drug-like” inhibitors of PPIs would be very valuable not only to enhance our understanding over physiological processes but also for drug discovery endeavors. However, PPIs were deemed intractable by LMW chemicals during many years. But today, with the new experimental and in silico technologies that have been developed, about 50 PPIs have already been inhibited by LMW molecules. Here, we first focus on general concepts about protein–protein interactions, present a consensual view about ligandable pockets at the protein interfaces and the possibilities of using fast and cost effective structure-based virtual screening methods to identify PPI hits. We then discuss the design of compound collections dedicated to PPIs. Recent financial analyses of the field suggest that LMW PPI modulators could be gaining momentum over biologics in the coming years supporting further research in this area.

In silico design of low molecular weight protein-protein interaction inhibitors: Overall concept and recent advances.

BCL-2: Long and winding path from discovery to therapeutic target.

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.

Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.

Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition

One approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with pro-apoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT-737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, ABT-199, that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl-1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies.

https://journals.sagepub.com/doi/pdf/10.1177/1087057114534070

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks’ protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg−1 and ∼43% at 60 mg kg−1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.

/pdf/glucose-based-spiro-oxathiazoles-as-in-vivo-anti-5ao0xv7eh4.pdf

Sophie Balzarin

Papers

Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737.

Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition