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Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg. Having identified an allosteric, induced pocket of IDH1, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate (), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. () has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer.Implications: Two novel potent and selective RSK inhibitors will now allow a full assessment of the potential of RSK as a therapeutic target for oncology. Mol Cancer Res; 12(5); 803-12. Ó2014 AACR. IntroductionThe p90 ribosomal S6 kinase (RSK) comprises a family of four closely related proteins that are widely expressed in cancer cell lines and tissues and are activated in response to a number of growth factors and hormones. RSK substrate phosphorylation has been functionally linked to cell survival, proliferation, and more recently to cell motility (1-4). RSK kinases have a unique structure containing two nonidentical kinase domains, N-terminal and C-terminal, separated by a linker region. The currently favored model for RSK activation entails ERK (extracellular signal-regulated kinase) phosphorylation of Thr573/577 (residue numbering for RSK1/ RSK2 amino acid sequence) in C-terminal kinase domain of RSK, which ultimately leads to a phosphorylation-based docking site for PDK1 in the hydrophobic motif of RSK on Ser380/386. PDK1 phosphorylation of residue Ser

A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure-activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.