PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.

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Brown adipose tissue (BAT) is considered an interesting target organ for the treatment of metabolic disease due to its high metabolic capacity. Non-shivering thermogenesis, once activated, can lead to enhanced partitioning and oxidation of fuels in adipose tissues, and reduce the burden of glucose and lipids on other metabolic organs such as liver, pancreas, and skeletal muscle. Sustained long-term activation of BAT may also lead to meaningful bodyweight loss. In this review, we discuss three different drug classes [the thiazolidinedione (TZD) class of PPARγ agonists, β3-adrenergic receptor agonists, and fibroblast growth factor 21 (FGF21) analogs] that have been proposed to regulate BAT and beige recruitment or activation, or both, and which have been tested in both rodent and human. The learnings from these classes suggest that restoration of functional BAT and beige mass as well as improved activation might be required to fully realize the metabolic potential of these tissues. Whether this can be achieved without the undesired cardiovascular side effects exhibited by the TZD PPARγ agonists and β3-adrenergic receptor agonists remains to be resolved.

Protein-protein interactions( PPIs) of 14-3-3 proteins are am odel system for studyingPPI stabilization. The complex natural product Fusicoccin As tabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter.H owever, drug-like 14-3-3PPI stabilizers enablingsuch studies have remainede lusive. An X-ray crystal structure of aP PI in complex with an extremelyl ow potencys tabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg 2 + leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency.T his originates from an ovel chelationcontrolled bioactive conformation stabilization effect. Metal chelation hasb een associated with pan-assayi nterference compounds (PAINS) and frequent hitter behavior,b ut chelation can evidently also lead to true potencyg ains and find use as am edicinal chemistry strategy to guidec ompound optimization. To demonstrate this, we exploited the effect to designt he first potent, selective, and drug-like 14-3-3 PPI stabilizers.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.10 mm Mg 2 + ."Fold increase" (y-axis)i st he mean fold-increase of signal over baseline (no (R)-2). (e)Ca 2 + (red triangles) and Mn 2 + (purple squares)a lso increase apparente fficacy of (R)-2 in 14-3-3/ERa(pT 594 )FPa ssay.

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