Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

Whiting, E. E.; Raje, Mithun; Chauhan, Jay; Wilder, Paul T.; Eker, Daniel Van; Hughes, Samuel; Bowen, Nathan G.; Vickers, Gregory; Fenimore, Ian C.; Fletcher, Steven

doi:10.1016/j.bmcl.2017.11.023

Cited by 16 publications

(9 citation statements)

References 43 publications

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“…In 2018, Whiting et al described a class of the hybrids of thiazolidine-2,4-dione and DE scaffolds based on the modification of a known dual Bcl-xL/Mcl-1 inhibitor featuring rhodanine. The bioactivity evaluation was indicative that the most active compound 33 (Figure ) showed extremely favorable inhibition toward both Mcl-1 ( K i = 155 nM) and Bcl-xL ( K i = 90 nM), showing a better dual inhibitory profile than that of the lead compound mentioned above . Above all, these DE-bearing compounds with Bcl-xL/Mcl-1 dual inhibitory effects provide a reference for the discovery of more clinical inhibitors targeting Bcl-2 antiapoptotic proteins, which may be more beneficial for cancer therapy and the solution of the existing drug-resistance.…”

Section: Application Of De Scaffold In Medicinal Chemistrymentioning

confidence: 92%

Diaryl Ether: A Privileged Scaffold for Drug and Agrochemical Discovery

Chen

Xiong

Yang

et al. 2020

J. Agric. Food Chem.

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Diaryl ether (DE) is a functional scaffold existing widely both in natural products (NPs) and synthetic organic compounds. Statistically, DE is the second most popular and enduring scaffold within the numerous medicinal chemistry and agrochemical reports. Given its unique physicochemical properties and potential biological activities, DE nucleus is recognized as a fundamental element of medicinal and agrochemical agents aimed at different biological targets. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antibacterial, antimalarial, herbicidal, fungicidal, insecticidal, and so on. In this review, we highlight the medicinal and agrochemical versatility of the DE motif according to the published information in the past decade and comprehensively give a summary of the target recognition, structure–activity relationship (SAR), and mechanism of action of its analogues. It is expected that this profile may provide valuable guidance for the discovery of new active ingredients both in drug and pesticide research.

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Section: Application Of De Scaffold In Medicinal Chemistrymentioning

confidence: 92%

Diaryl Ether: A Privileged Scaffold for Drug and Agrochemical Discovery

Chen

Xiong

Yang

et al. 2020

J. Agric. Food Chem.

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“…Towards a more selective multi‐target drug, rhodanine is replaced with TZD. The results showed that compound 130 has higher potency and selectivity profile when compared with rhodanine derivatives BH3I – 1 and 129 [119] …”

Section: Synthesis Of 24‐thiazolidinedione Ringmentioning

confidence: 99%

Chemistry and Applications of Functionalized 2,4‐Thiazolidinediones

et al. 2023

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Thiazolidinedione (TZD) is one of the privileged heterocyclic rings and has shown many biological applications in medicinal chemistry and drug discovery. This review covers the synthetic approaches of TZD and its derivatives, different synthetic techniques for affording the desired regioselectivity and stereoselectivity, and the techniques that would enhance reaction conditions such as microwave, one‐pot, or ultrasound synthesis. It focuses on synthetic challenges of glitazones and the transformation of other heterocycles to TZD. Moreover, the chemical and biological behavior of TZD through the substitution in the N3 position, modification of the C5 position, annealing in complex heterocyclic systems, and hybridization with other pharmacologically attractive moieties are discussed. All reactions mentioned are provided as possible with different reaction conditions, mechanisms, derivatives scope, yield and clarified by applications of such reactions in the construction of potential medicinal agents. The review also answers questions about rapid racemization of glitazones, their toxicity, considering TZD as pan‐assay interference compounds (PAINS) or not, and the influence of saturation of 5‐position of TZD in their biological activities. This review is a comprehensive guide to make informed decisions for construction of TZD derivatives with biological potentials.

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“…EC 50 ) and only used those clear biophysical K D or K i values. This search criteria yielded 66 compounds [6,7,23,35–38,40,44–46,55,57,59,60,62,63,70–75,77–131]. Each of these inhibitors was then manually categorized as being either a small molecule, peptide or belonging to neither group.…”

Section: Analysis Of Recent Ppi Inhibitors: Molecular Mass Potency Amentioning

confidence: 99%

Inhibitors of protein–protein interactions (PPIs): an analysis of scaffold choices and buried surface area

Gestwicki

2018

Current Opinion in Chemical Biology

215

185

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Protein-protein interactions (PPI) were once considered 'undruggable', but clinical successes, driven by advanced methods in drug discovery, have challenged that notion. Here, we review the last three years of literature on PPI inhibitors to understand what is working and why. From the 66 recently reported PPI inhibitors, we found that the average molecular weight was significantly greater than 500Da, but that this trend was driven, in large part, by the contribution of peptide-based compounds. Despite differences in average molecular weight, we found that compounds based on small molecules or peptides were almost equally likely to be potent inhibitors (K<1μM). Finally, we found PPIs with buried surface area (BSA) less than 2000Å were more likely to be inhibited by small molecules, while PPIs with larger BSA values were typically inhibited by peptides. PPIs with BSA values over 4000Å seemed to create a particular challenge, especially for orthosteric small molecules. Thus, it seems important to choose the inhibitor scaffold based on the properties of the target interaction. Moreover, this survey suggests a (more nuanced) conclusion to the question of whether PPIs are good drug targets; namely, that some PPIs are readily 'druggable' given the right choice of scaffold, while others still seem to deserve the 'undruggable' moniker.

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Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

Cited by 16 publications

References 43 publications

Diaryl Ether: A Privileged Scaffold for Drug and Agrochemical Discovery

Diaryl Ether: A Privileged Scaffold for Drug and Agrochemical Discovery

Chemistry and Applications of Functionalized 2,4‐Thiazolidinediones

Inhibitors of protein–protein interactions (PPIs): an analysis of scaffold choices and buried surface area

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