Small Molecules and Their Role in Effective Preclinical Target Validation

Clegg, Michael A.; Tomkinson, Nicholas C. O.; Prinjha, Rab K.; Humphreys, P. G.

doi:10.4155/fmc-2017-0121

Cited by 3 publications

(5 citation statements)

References 18 publications

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“…yield, 50 which was then oxidized using 1,3-dichloro-5,5dimethylimidazolidine-2,4-dione to afford sulfonyl chloride 64 in five steps with 16% overall yield. 51 This could then be used in a series of DIPEA mediated sulfonamidations to synthesize the desired products (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)23).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13] Work in our group has recently been focused on developing tool molecules for the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome region, candidate 2 (CECR2) bromodomains, with a particular focus on novel chemotypes. [14][15][16] ATAD2 is a promising oncogene which is overexpressed in multiple, unrelated human cancers. [17][18] Protein knockdown experiments have linked ATAD2 to cell survival, proliferation and migration pathways.…”

Section: Introductionmentioning

confidence: 99%

“…However, the BET family represents just 8 of the 61 known human bromodomains; therefore, it is logical to propose that other bromodomains may control the expression of genes crucial to other diseases. − Despite this promising hypothesis, the pharmacological relevance of inhibiting these bromodomains using small molecules is still largely unknown. Therefore, before investment in a full drug discovery program, these targets need to be fully validated. − Work in our group has recently been focused on developing tool molecules for the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) bromodomains, with a particular focus on novel chemotypes. − …”

Section: Introductionmentioning

confidence: 99%

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Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

et al. 2020

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Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules.Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

et al. 2020

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“…The generation of high quality chemical probes, and the structural information typically obtained during their development, has also facilitated the evolution of more sophisticated bifunctional chemical biology tools. These include bivalent inhibitors, proteolysis targeting chimeras (PROTACs) and photoaffinity probes which can provide additional information into the validation of biological targets and, through the use of complementary techniques such as Chem‐seq, map the interactions between small molecules and the human genome …”

Section: Introductionmentioning

confidence: 99%

“…These include bivalent inhibitors, proteolysist argeting chimeras (PROTACs) and photoaffinity probes which can provide additional information into the validation of biological targets and, through the use of complementary techniques such as Chemseq, map the interactions between small molecules and the human genome. [16,17] All non-BET bromodomain targeted molecules disclosed between December 2015 and October 2018 shall be reviewed here with close attention to the aforementioned criteria, notinga ny opportunities for future probe development and their applicability as chemical probesf or target validation. For readerc larity,a ll bromodomaini nhibitorsh aveb een drawn (wherep ossible) with the acetylated lysine mimetic in the top-left/bottom-left cornera nd, when available, ac rystal structure of the inhibitor bound to the target protein has been included.…”

Section: Introductionmentioning

confidence: 99%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

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Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras

Xia

Liu

et al. 2019

Future Med. Chem.

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Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

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Small Molecules and Their Role in Effective Preclinical Target Validation

Cited by 3 publications

References 18 publications

Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras

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