Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.

/pdf/targeting-transcription-regulation-in-cancer-with-a-covalent-41jsawoiak.pdf

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

http://csmres.co.uk/cs.public.upd/article-downloads/Shifting-from-the-single-to-the.pdf

Shifting from the single to the multitarget paradigm in drug discovery.

Rho kinases (ROCKs) belong to the serine–threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiological and biological functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.

Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential

Recent Advances in the Chemistry of Indazoles

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

L'invention concerne des composes de formule (I), dans laquelle les variables son specifiees. Lesdits composes peuvent se lier a des proteases aspartiques de maniere a inhiber leur activite. Ils sont utilises dans le traitement ou l'amelioration de maladies associees a l'activite de la protease aspartique. L'invention concerne egalement des methodes de traitement par antagonisme des inhibiteurs de la protease aspartique chez un sujet necessitant les soins, comprenant l'administration au sujet d'une quantite efficace de maniere therapeutique d'un compose de formule (I).

Inhibiteurs de la rénine

Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition

Epigenetic gene regulation is a critical process controlling differentiation and development, the malfunction of which may underpin a variety of diseases. In this article, we review the current landscape of small-molecule epigenetic modulators including drugs on the market, key compounds in clinical trials, and chemical probes being used in epigenetic mechanistic studies. Hit identification strategies for the discovery of small-molecule epigenetic modulators are summarized with respect to writers, erasers, and readers of histone marks. Perspectives are provided on opportunities for new hit discovery approaches, some of which may define the next generation of therapeutic intervention strategies for epigenetic processes.

https://journals.sagepub.com/doi/pdf/10.1177/1087057112437763

Perspectives on the Discovery of Small-Molecule Modulators for Epigenetic Processes:

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Papers

Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

Inhibiteurs de la rénine

Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition

Perspectives on the Discovery of Small-Molecule Modulators for Epigenetic Processes: