Histone deacetylase (HDAC) inhibitor specificity determinants are preserved in a class of dual HDAC/non-covalent proteasome inhibitors.

Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors.

1-Sulfonylated 1,2,3,4-tetrahydroquinoline-6-carboxylic acids as simple, readily-accessible MCL-1 inhibitors.

MCL-1 is a member of the BCL-2 family of proteins that regulates the mitochondrial pathway of apoptosis. Overexpression of MCL-1 is associated with the development and progression of a range of human cancers, and is also responsible for the onset of resistance to conventional chemotherapies. Although several MCL-1 inhibitors have now advanced to clinical trials, recent suspensions and terminations reveal the urgency with which new inhibitor chemotypes must be discovered. Building on our previous studies of a chiral, isomeric lead, we report the discovery of a new chemotype to inhibit MCL-1: 1-sulfonylated 1,2,3,4-tetrahydroquinoline-6-carboxylic acid. The nature of the sulfonyl moiety contributed significantly to the resulting inhibitory ability. For example, transforming a phenylsulfonyl group into a 4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl moiety elicited more than a 73-fold enhancement in inhibiton of MCL-1, possibly through targeting the p2 pocket in the BH3-binding groove, and so it is anticipated that further structure-activity studies here will lead to continued improvements in binding. It should be underscored that this class of MCL-1 inhibitors is readily accessible in four simple steps, is achiral and offers many avenues for optimization, all factors that are welcomed in the search for safe and effective inhibitors of this driver of cancer cell survival.

Recent applications of covalent chemistries in protein-protein interaction inhibitors.

Protein-protein interactions (PPIs) are large, often featureless domains whose modulations by small-molecules are challenging. Whilst there are some notable successes, such as the BCL-2 inhibitor venetoclax, the requirement for larger ligands to achieve the desired level of potency and selectivity may result in poor "drug-like" properties. Covalent chemistry is presently enjoying a renaissance. In particular, targeted covalent inhibition (TCI), in which a weakly electrophilic "warhead" is installed onto a protein ligand scaffold, is a powerful strategy to develop potent inhibitors of PPIs that are smaller/more drug-like yet have enhanced affinities by virtue of the reinforcing effect on the existing non-covalent interactions by the resulting protein-ligand covalent bond. Furthermore, the covalent bond delivers sustained inhibition, which may translate into significantly reduced therapeutic dosing. Herein, we discuss recent applications of a spectrum of TCIs, as well as covalent screening strategies, in the discovery of more effective inhibitors of PPIs using the HDM2 and BCL-2 protein families as case studies.

Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6.

Multi-factorial diseases are illnesses that exploit multiple cellular processes, or stages within one process, and thus highly targeted therapies often succumb to the disease, losing efficacy as resistance sets in. Combination therapies have become a mainstay to battle these diseases, however these regimens are plagued with caveats. An emerging avenue to treat multi-factorial diseases is polypharmacology, wherein a single drug is rationally designed to bind multiple targets, and is widely touted to be superior to combination therapy by inherently addressing the latter's shortcomings, which include poor patient compliance, narrow therapeutic windows and spiraling healthcare costs. Through its roles in intracellular trafficking, cell motility, mitosis, protein folding and as a back-up to the proteasome pathway, HDAC6 has rapidly become an exciting new target for therapeutics, particularly in the discovery of new drugs to treat Alzheimer's disease and cancer. Herein, we describe recent efforts to marry together HDAC pharmacophores, with a particular emphasis on HDAC6 selectivity, with those of other targets towards the discovery of potent therapeutics to treat these evasive diseases. Such polypharmacological agents may supercede combination therapies through inherent synergism, permitting reduced dosing, wider therapeutic windows and improved compliance.