Molecular docking is an invaluable tool in modern drug discovery. This review focuses on methodological developments relevant to the field of molecular docking. The forces important in molecular recognition are reviewed and followed by a discussion of how different scoring functions account for these forces. More recent applications of computational chemistry tools involve library design and database screening. Last, we summarize several critical methodological issues that must be addressed in future developments.

We report on the development and validation of a new version of DOCK. The algorithm has been rewritten in a modular format, which allows for easy implementation of new scoring functions, sampling methods and analysis tools. We validated the sampling algorithm with a test set of 114 protein-ligand complexes. Using an optimized parameter set, we are able to reproduce the crystal ligand pose to within 2 A of the crystal structure for 79% of the test cases using our rigid ligand docking algorithm with an average run time of 1 min per complex and for 72% of the test cases using our flexible ligand docking algorithm with an average run time of 5 min per complex. Finally, we perform an analysis of the docking failures in the test set and determine that the sampling algorithm is generally sufficient for the binding pose prediction problem for up to 7 rotatable bonds; i.e. 99% of the rigid ligand docking cases and 95% of the flexible ligand docking cases are sampled successfully. We point out that success rates could be improved through more advanced modeling of the receptor prior to docking and through improvement of the force field parameters, particularly for structures containing metal-based cofactors.

Aberrant signaling through the fi broblast growth factor 19 (FGF19)/fi broblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplifi cation as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplifi cation. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β ( KLB ) could potentially respond to treatment with an FGFR4 inhibitor. These fi ndings are the fi rst demonstration of a therapeutic strategy that targets a subset of patients with HCC. SIGNIFICANCE:This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifi cally targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is effi cacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the fi rst FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling. Cancer Discov; 5(4);

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and (gastrointestinal stromal tumor) activation loop mutations.

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.