Month: May 2020

Secreted BMP Antagonists and Their Role in Cancer and Bone Metastases

Grace M Todd, Zhichun Gao, Marko Hyvönen, Derek P Brazil, Peter Ten Dijke

Bone 137:115455 (2020)
DOI: 10.1016/j.bone.2020.115455
Pubmed: 32473315


Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. Continue reading →

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Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Sarah L. Kidd, Elaine Fowler, Till Reinhardt, Thomas Compton, Natalia Mateu, Hector Newman, Dom Bellini, Romain Talon, Joseph McLoughlin, Tobias Krojer, Anthony Aimon, Anthony Bradley, Michael Fairhead, Paul Brear, Laura Díaz-Sáez, Katherine McAuley, Hannah F. Sore, Andrew Madin, Daniel H. O’Donovan, Kilian V. M. Huber, Marko Hyvönen, Frank von Delft, Christopher G. Dowson and David R. Spring

Chemical Science 11, 10792-10801 (2020)
DOI: 10.1039/D0SC01232G

PDB coordinates: 6Y6O (3D view),6Y6N (3D view)


Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Continue reading →

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Diarylethene Moiety as an Enthalpy-Entropy Switch: Photoisomerizable Stapled Peptides for Modulating p53/MDM2 Interaction

Alexander V Strizhak, Oleg Babii, Sergii Afonin, Iuliia Bakanovic, Teodors Pantelejevs, Wenshu Xu, Elaine Fowler, Rohan Eapen, Krishna Sharma, Maxim O Platonov, Vasyl V Hurmach, Laura Itzhaki, Marko Hyvönen, Anne S Ulrich, David R Spring, Igor V Komarov

Organic and Biomolecular Chemistry, 2020 May 11, Advance article in press
DOI: 10.1039/d0ob00831a
Pubmed: 32390036

PDB coordinates: 6y4q (3D view)


Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the “open” configuration, but up to eight times larger for the corresponding “closed” isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Continue reading →

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