Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix.

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer.

Purpose: Given that osimertinib is the only approved third-generation EGFR-TKI against activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models.

Experimental Design: Antitumor activity of YH25448 was investigated using mutant -expressing Ba/F3 cells and various lung cancer cell lines.

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.

Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials.

Correction: Crystal Structure of Pim1 Kinase in Complex with a Pyrido[4,3-D]Pyrimidine Derivative Suggests a Unique Binding Mode.

[This corrects the article DOI: 10.1371/journal.pone.

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer.

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib).

Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs.

Unlabelled: Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers.

Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors.

A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.

G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia.

Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection.

Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.

Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1.

Synthesis and structure-activity relationship of aminopyridines with substituted benzoxazoles as c-Met kinase inhibitors.

A series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent benzoxazole scaffold, with particular focus on the hydroxyl substituent of the benzoxazole moiety.

Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities.

Metabolism of LB42908, a novel farnesyl transferase inhibitor, was investigated for preclinical development. In vitro hepatic metabolism of LB42908 gave rise to at least 9 metabolites via phase I biotransformation pathways, which were characterized by HPLC-UV, LC-MS, and LC-MS/MS analyses. N-Dealkylation was shown to be a major phase I metabolic pathway.

Phosphatase of regenerating liver-3 promotes migration and invasion by upregulating matrix metalloproteinases-7 in human colorectal cancer cells.

Phosphatase of regenerating liver (PRL)-3, a member of a subgroup of protein tyrosine phosphatases that can stimulate the degradation of the extracellular matrix, is over-expressed in metastatic colorectal cancer (CRC) relative to primary tumors. To determine whether PRL-3-induced enhancement of migration and invasion is dependent on the expression of matrix metalloproteinases (MMPs), PRL-3 was expressed in DLD-1 human CRC cells. The motility, migration and invasion characteristics of the cells were examined, and metastasis to the lung was confirmed in a nude mouse using PRL-3-overexpressing DLD-1 cells [DLD-1 (PRL-3)].

Design and synthesis of triazolopyridazines substituted with methylisoquinolinone as selective c-Met kinase inhibitors.

A series of triazolopyridazines substituted with methylisoquinolinone were designed and synthesized. Some of the triazolopyridazines strongly inhibited c-Met kinase and showed good anti-proliferative activity against a panel of c-Met-amplified gastric cancer cell lines (MKN-45, SNU-5 and Hs746T).

Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo.

Kinases have been studied as potential cancer targets because they play important roles in the cellular signaling of tumors. A number of small molecules targeting kinases are prescribed in clinics and many kinase inhibitors are being evaluated in the clinical phase. Previously, we discovered a series of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors.

Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors.

We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats.

Prognostic significance of c-Met expression in glioblastomas.

Background: The authors investigated whether expression of c-Met protein in glioblastomas is associated with overall survival and biologic features representing tumor invasiveness in patients with glioblastomas.

Methods: Paraffin-embedded specimens of glioblastomas from 62 patients treated in a single institution were assessed by immunohistochemical (IHC) analysis of c-Met expression. On the basis of the clinical data for these patients, the association between c-Met expression and clinicobiologic features representing tumor invasiveness was analyzed.

Synthesis, SAR, and X-ray structure of novel potent DPPIV inhibitors: oxadiazolyl ketones.

Synthesis of a novel series of DPPIV inhibitors with 1,2,4- and 1,3,4-oxadiazolyl ketone derivatives and its structure-activity relationships are discussed. Compound 18h showed good inhibitory activity against DPPIV and favorable pharmacokinetic properties. In vivo pharmacodynamic efficacy and co-crystal structure of compound 18h with DPPIV is also described.

Design and synthesis of oxime ethers of alpha-acyl-beta-phenylpropanoic acids as PPAR dual agonists.

Oxime ethers of alpha-acyl-beta-phenylpropanoic acids were prepared to apply as PPARalpha and gamma dual agonists. Among them, compound 11l proved to exhibit potent in vitro activities with EC(50) of 19 and 13nM in PPARalpha and gamma, respectively. It showed better glucose lowering effects than rosiglitazone 1 and ameliorated the lipid profile like plasma triglyceride in db/db mice model.

The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells.

LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s).

Hydantoin derivatives as non-peptidic inhibitors of Ras farnesyl transferase.

1,3,5,5-Tetrasubstituted 2,4-imidazolinedione (hydantoin) derivatives were evaluated as Ftase inhibitors. Potent Ftase inhibitors without thiol or peptide were obtained in three steps.

Confirmation of a linkage between H-Ras and MMP-13 expression as well as MMP-9 by chemical genomic approach.

As farnesylation of the Ras protein by farnesyl transferase is a critical step for the Ras functional activity, the farnesyl transferase inhibitor could affect H-Ras functions and the inhibitors such as arteminolide, SCH66336 and LB42908 completely inhibited Ras-farnesylation. However, they did not induce apoptosis of H-Ras-transformed cells with concentration for blocking H-Ras farnesylation. To determine the antitumor effects of the inhibitors, it was analyzed through the expression profile of genes, regulated by activated H-Ras or FTIs by using cDNA microarray.

Enhancement of interleukin-12 gene-based tumor immunotherapy by the reduced secretion of p40 subunit and the combination with farnesyltransferase inhibitor.

Interleukin-12 (IL-12) gene was shown to produce both IL-12 and p40 subunit. The excess production of the p40 subunit as a natural antagonist of IL-12 is a major obstacle of IL-12 gene-based cancer therapy. We previously reported that IL-12N220L gene, which selectively reduces the secretion of the p40 subunit, induces long-lasting stronger type 1 helper T cells (T(H)1) and cytotoxic T lymphocyte (CTL) immunity in hepatitis C virus (HCV) E2 DNA vaccination model and higher protection from challenge with tumor cells expressing E2 than IL-12 in a prophylactic setting.

Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21(ras)-dependent NF-kappaB activation.

Farnesylation of p21(ras) is an important step in the intracellular signaling pathway of growth factors, hormones, and immune stimulants. We synthesized a potent and selective farnesyltransferase inhibitor (LB42708) with IC(50) values of 0.8 nM in vitro and 8 nM in cultured cells against p21(ras) farnesylation and examined the effects of this inhibitor in the settings of inflammation and arthritis.