Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression

Zhou, Bing; Hu, Jiantao; Xu, Fuming; Chen, Zhuo; Bai, Longchuan; Fernández‐Salas, Ester; Lin, Mei; Liu, Liu; Yang, Chao; Zhao, Yujun; McEachern, Donna; Przybranowski, Sally; Wen, Bo; Sun, Duxin; Wang, Shaomeng

doi:10.1021/acs.jmedchem.6b01816

Cited by 305 publications

(308 citation statements)

References 30 publications

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“…Superior efficacy compared to BET inhibition was also observed for a pomalidomide based PROTAC comprising a second generation BET inhibitor which induces growth inhibition and apoptosis in triple-negative breast cancers (TNBC) (Bai et al, 2017). Tethering this second generation BET inhibitor to lenalidomide resulted in PROTACs degrading BET proteins at picomolar concentration which caused >90% tumor regression in acute leukemia mouse xenograft models (Zhou et al, 2017). These studies highlight the therapeutic advantage of event -driven pharmacology given that BRD4 inhibition is often counteracted by compensatory BRD4 overexpression to hamper inhibitor efficacy (Shimamura et al, 2013).…”

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

327

261

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Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell’s own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

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Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

327

261

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“…Molecules which bind to an E3 ubiquitin ligase are also of great interest to the field of targeted protein degradation, particularly as recruiting elements for proteolysis targeting chimera (PROTACs) . Indeed, IMiDs have been widely used as E3 recruiting elements to enable the degradation of a wide variety of targets …”

Section: Figurementioning

confidence: 99%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

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“…Furthermore, studies with BET degraders demonstrated potent inhibition of cancer cell growth and the induction of apoptosis when compared to the corresponding BET inhibitors. 24, 25, 27, 38 …”

mentioning

confidence: 99%

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

Robb¹,

Contreras²,

Kour³

et al. 2017

Chem. Commun.

185

141

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Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9.

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Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression

Cited by 305 publications

References 30 publications

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

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