nvp-tae684 and Neoplasms

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC

Topics: Amination; Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Isoindoles; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrimidines; Receptor Protein-Tyrosine Kinases

The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 μM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Small Molecule Libraries; Structure-Activity Relationship

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Topics: Anaplastic Lymphoma Kinase; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dogs; Humans; Macaca fascicularis; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Sulfones; Xenograft Model Antitumor Assays

Topics: Anaplastic Lymphoma Kinase; Animals; Humans; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were ineffective against unselected cell lines but exhibited dramatic cell killing of small nonoverlapping subsets. Cells with exquisite sensitivity to EGFR, HER2, MET, or BRAF kinase inhibitors were marked by activating mutations or amplification of the drug target. Although most cell lines recapitulated known tumor-associated genotypes, the screen revealed low-frequency drug-sensitizing genotypes in tumor types not previously associated with drug susceptibility. Furthermore, comparing drugs thought to target the same kinase revealed striking differences, predictive of clinical efficacy. Genetically defined cancer subsets, irrespective of tissue type, predict response to kinase inhibitors, and provide an important preclinical model to guide early clinical applications of novel targeted inhibitors.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genotype; Humans; Neoplasms; Protein Kinase Inhibitors