The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.

Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC.

YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.

Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L.

YM-359445, an orally bioavailable vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, has highly potent antitumor activity against established tumors.

Purpose: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase. The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo.

(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.

A role of androgen receptor protein in cell growth of an androgen-independent prostate cancer cell line.

Prostate cancer, which develops due to androgen and is initially responsive to androgen deprivation therapy, often comes to acquire androgen deprivation therapy resistance in short order. We investigated the role of androgen receptor (AR) protein in an androgen-independent prostate cancer cell line using AR ligands and AR siRNA. Although the androgen-independent cell line scarcely responded to AR ligands, their growth was attenuated by ablation of AR protein by siRNA.

YM-231146, a novel orally bioavailable inhibitor of vascular endothelial growth factor receptor-2, is effective against paclitaxel resistant tumors.

Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition.

YM-201627: an orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation.

We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039-0.

Human expanded polyglutamine androgen receptor mutants in neurodegeneration as a novel ligand target.

Androgen receptor (AR) plays key roles in various biological events, including pathological processes such as prostate cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy (SBMA). SBMA is caused by mutation of the expanded polyglutamine (polyQ) stretches in the AR gene. Recently, we established a Drosophila SBMA model that expresses the expanded polyQ hAR mutant in eyes, which monitors neurodegeneration as a rough eye phenotype.

N-Arylpiperazine-1-carboxamide derivatives: a novel series of orally active nonsteroidal androgen receptor antagonists.

A novel series of N-arylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Reporter assays indicated that trans-2,5-dimethylpiperazine derivatives are potent AR antagonists, and in this series trans-N-4-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide (18 g, YM-175735) exhibited the most potent antiandrogenic activity. Compared to bicalutamide, YM-175735 is an approximately 4-fold stronger AR antagonist and has slightly increased antiandrogenic activity, suggesting that YM-175735 may be useful in the treatment of prostate cancer.

Synthesis and pharmacological evaluation of novel arylpiperazine derivatives as nonsteroidal androgen receptor antagonists.

The search for novel antiandrogens by high-throughput screening (HTS) of the Yamanouchi chemical library led to the discovery of the lead compound (5), which possesses an arylmorpholine moiety. Through the optimization of the lead compound (5), we have found a series of novel arylpiperazine derivatives. Among them, 4-[4-cyano-(3-trifluoromethyl)phenyl]-N-(4-fluorophenyl)piperazine-1-carboxamide (22; YM-92088) exhibited a potent AR antagonistic activity with an IC(50) value of 0.

Stabilization of androgen receptor protein is induced by agonist, not by antagonists.

The action of nuclear receptor ligands in target tissues is specified mainly by the expression levels of their cognate nuclear receptors. The expression levels of these receptors are controlled through transcriptional and post-transcriptional events. Among post-transcriptional events, the effect of ligand on nuclear receptor protein turnover still remains largely unknown.

Bag1 proteins regulate growth and survival of ZR-75-1 human breast cancer cells.

Bag1 proteins bind heat shock protein M(r) 70,000 (Hsp 70) family molecular chaperones and regulate diverse pathways involved in cell proliferation, apoptosis, and stress responses. Four isoforms of Bag1 can be produced from a single gene in humans, including a nuclear-targeted long version (Bag1L)and a shorter cytosolic isoform (Bag1). Because overexpression of Bag1and Bag1L has been reported in breast cancers, we explored the effects of Bag1 and Bag1L on the growth of ZR-75-1 human breast cancer cells cultured in vitro and in tumor xenograft models using immunocompromised mice.