The Exploration of Chirality for Improved Druggability within the Human Kinome

Abstract

Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.

Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur–Fluorine Exchange (SuFEx) Reaction

“…Directional interactions are crucial to the development of active ingredients in pharmaceutical and agrochemical products. Inclusion of chiral moieties can increase complementarity and hence potency and selectivity of a compound for a biological target . In contrast to sulfones and sulfonamides, their chiral aza‐analogues, that is, sulfoximines and sulfonimidamides (Figure a), have been underrepresented in the life sciences despite their beneficial chemical properties .…”

Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered by a Fragment Optimization Approach

“…[14,15] Perceiving the plasticity of pyrazoloadenines, we sought to use a pyrazoloadenine fragment library to test a fragment-based discovery approach by screening the library against the RET kinase. With our prior interest in developing kinase inhibitors, [16][17][18][19] a pyrazoloadenine-based fragment library was screened against RET in biochemical assays as well as cellular assays employing LC-2/ad, a RET-CCDC6 fusion-driven NSCLC cell line, and matched controls to determine oncoprotein specificity (TRKdriven, KM-12) and cytotoxicity (A549). This approach led to the discovery of 8 p, a highly potent and selective pyrazoloadeninebased inhibitor of RET.…”

Ab Initio Spectroscopic Investigation of Pharmacologically Relevant Chiral Molecules: The Cases of Avibactam, Cephems, and Idelalisib as Benchmarks for Antibiotics and Anticancer Drugs

“…Chirality , a property related to the lack of planes of symmetry and inversion centers, plays an important role in molecular recognition; therefore, it is of interest for pharmaceutical science [12], catalysis in chemical industry, and biomolecular function. One enantiomer (i.e., either of two nonsuperimposable mirror images of a chiral drug molecule) may indeed correctly bind in the target binding site, yielding the desired pharmacologic effect, while the other enantiomer may not fit into the binding site, being thus inactive, or it may even interact with a different site causing adverse effects (e.g., [12] and refs therein). The ability to distinguish between enantiomers of a given chiral molecule can therefore be crucial in drug design and production.…”

“…The ability to distinguish between enantiomers of a given chiral molecule can therefore be crucial in drug design and production. In specific classes of molecules, such as kinase inhibitors, chiral drug discovery has attracted attention as a method to improve drug molecules, e.g., in terms of solubility or pharmacokinetic profiles [12]. In the case of idelalisib, its chiral character has been reported as contributing to its selectivity towards the PI3Kδ kinase [12].…”