Smallest Maximum Intramolecular Distance: A Novel Method to Mitigate Pregnane Xenobiotic Receptor Activation.

Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.

Prediction of Protein Pairs Sharing Common Active Ligands Using Protein Sequence, Structure, and Ligand Similarity.

We benchmarked the ability of comparative computational approaches to correctly discriminate protein pairs sharing a common active ligand (positive protein pairs) from protein pairs with no common active ligands (negative protein pairs). Since the target and the off-targets of a drug share at least a common ligand, i.e., the drug itself, the prediction of positive protein pairs may help identify off-targets. We evaluated representative protein-centric and ligand-centric approaches, including (1) 2D and 3D ligand similarity, (2) several measures of protein sequence similarity in conjunction with different sequence sources (e.g., full protein sequence versus binding site residues), and (3) a newly described pocket shape similarity and alignment program called SiteHopper. While the sequence-based alignment of pocket residues achieved the best overall performance, SiteHopper outperformed sequence-based approaches for unrelated proteins with only 20-30% pocket residue identity. Analogously, among ligand-centric approaches, path-based fingerprints achieved the best overall performance, but ROCS-based ligand shape similarity outperformed path-based fingerprints for structurally dissimilar ligands (Tanimoto 25%-40%). A significant drop in recognition performance was observed for ligand-centric approaches when PDB ligands were used instead of ChEMBL ligands. Finally, we analyzed the relationship between pocket shape and ligand shape in our data set and found that similar ligands tend to bind to similar pockets while similar pockets may accept a range of different-shaped ligands.

Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors.

Herein, we report a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors. Starting with molecule 5, we have applied structure-based drug design principles to identify the triazolothiadiazole ring system. We successfully replaced the metabolically unstable phenolic moiety with a quinoline group. Further optimization around the 5,6 bicyclic moiety led to the identification of 21. Compound 21 suffered from PDE3 selectivity issues and subsequent, structurally informed design led to the discovery of compound 23. Compound 23 has exquisite kinase selectivity, excellent potency, favorable ADME profile, and showed dose-dependent antitumor efficacy in a SNU-5 gastric cancer xenograft model.

Discovery of a Novel Series of Potent and Selective Alkynylthiazole-Derived PI3Kγ Inhibitors.

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Kγ plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3Kγ inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3Kγ potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as 14 and 32, highly potent, subtype selective, and CNS penetrant PI3Kγ inhibitors. Compound 14 showed robust inhibition of PI3Kγ mediated neutrophil migration in vivo.

Synthesis of a 6-Aza-Isoindolinone-Based Inhibitor of Phosphoinositide 3-Kinase γ via Ruthenium-Catalyzed [2 + 2 + 2] Cyclotrimerization.

Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.

Tuning out of hERG.

A number of drug withdrawals in recent years have been related to cardiovascular toxicity associated with undesirable blockade of the hERG potassium channel. A promiscuous target, hERG has been demonstrated to interact with pharmaceuticals of widely varying structure. Computational and statistical modeling efforts encompassing homology modeling, pharmacophore and quantitative structure-activity relationship models, and also various classification methods, are aimed at defining the molecular features that confer hERG inhibitory activity and understanding the structure-activity relationships that govern hERG-drug interactions. The organization-wide adoption of hERG models is driven by their ability to produce specific and testable structural hypotheses that lead to compounds devoid of hERG liability.

Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology.

Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. We investigated the phenomenon of kinase-likeness, i.e., the propensity of ligands to inhibit protein kinases, in the context of kinase-specific substructural fragments. The frequency of occurrence of multiple structural fragments in kinase inhibitor libraries relative to nonkinase compounds has been analyzed. A combination of structural fragment counts, termed the "2-0" kinase-likeness rule, provides approximately 5-fold enrichment in kinase active compounds. This rule has been validated using in-house kinase counterscreening data and applied prospectively to uncover kinase activities in marketed drugs. In addition, the role of discriminating fragments in kinase recognition was interrogated using available structural data, providing an insight into their effect on inhibitor potency and selectivity. One of these fragments, bisarylaniline, has been characterized as a kinase-privileged fragment with specific binding preferences and a link to increased activity within kinases.

Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications.

This corrects the article DOI: 10.1038/nrd.2017.194.

Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications.

The productivity of the pharmaceutical industry has been widely discussed in recent years, particularly with regard to concerns that substantial expenditures on research and development have failed to translate into approved drugs. Various analyses of this productivity challenge have focused on aspects such as attrition rates at particular clinical phases or the physicochemical properties of drug candidates, but relatively little attention has been paid to how the industry has performed from the standpoint of the choice of therapeutic mechanisms and their intended indications. This article examines what the pharmaceutical industry has achieved in this respect by analysing comprehensive industry-wide data on the mechanism-indication pairs that have been investigated during the past 20 years. Our findings indicate several points and trends that we hope will be useful in understanding and improving the productivity of the industry, including areas in which the industry has had substantial success or failure and the relative extent of novelty in completed and ongoing projects.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.

The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib).

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAFV600E-mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242, and NCT02608229). Mol Cancer Ther; 16(11); 2351-63. ©2017 AACR.

Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers.

In silico approaches are widely used to predict human ether-a-go-go-related gene (hERG) channel blockade. Published pharmacophore models of hERG blockers typically contain a basic nitrogen center flanked by aromatic or hydrophobic groups. However, hERG blockade has been observed in series lacking the basic nitrogen. By utilizing screening data for 194 potent uncharged hERG actives, we propose a pharmacophore for neutral hERG blockers, and provide guidance on eliminating hERG liability in an uncharged hERG active chemical series.

Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 µM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 µM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

Predictive in silico modeling for hERG channel blockers.

hERG-mediated sudden death as a side effect of non-antiarrhythmic drugs has been receiving increased regulatory attention. Perhaps owing to the unique shape of the ligand-binding site and its hydrophobic character, the hERG channel has been shown to interact with pharmaceuticals of widely varying structure. Several in silico approaches have attempted to predict hERG channel blockade. Some of these approaches are aimed primarily at filtering out potential hERG blockers in the context of virtual libraries, others involve understanding structure-activity relationships governing hERG-drug interactions. This review summarizes the most recent efforts in this emerging field.

Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.

Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.

Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.

We present a novel method for stepwise scaffold assembly that integrates fragment-by-fragment ligand design approaches with high-throughput virtual library screening (COREGEN). As an extension of our earlier studies of common features present in drug molecules, we investigate the hypothesis that most pharmaceutically interesting ligands can be expressed in terms of the ring-linker frameworks that comprise them. Analysis of 119 published kinase inhibitors from at least 18 different targets illustrates that a basis set of 4 rings and 8 linkers is sufficient to describe approximately 90% of ring and linker occurrences, respectively. A similar result was derived from a larger set of approximately 40,000 kinase inhibitors from curated patents. A method for ring-linker-based assembly of scaffold libraries that uses experimental information to guide the placement of anchor fragments is validated using a set of reported kinase inhibitors of Bcr-Abl, Cdk2, and Src. In every case, the predominant structural motif of reported ligand cores is reproduced and variations are suggested. To underscore generality of this approach, a novel scaffold for a cyclooxygenase-2 (COX-2) selective ligand is proposed.

Toward a pharmacophore for kinase frequent hitters.

Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. One of the hardest challenges in kinase inhibitor design is achieving target selectivity. By utilizing X-ray structural information for four promiscuous inhibitors, we propose a five-point pharmacophore for kinase frequent hitters, demonstrate its ability to discriminate between frequent hitters and selective ligands, and suggest a strategy for selective inhibitor design.