Display omitted
Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup ...molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.
Display omitted
A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic ...heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential ...therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzob1,4diazepin-2-one.
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full ...antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule
(GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of
that showed ionic interaction of azetidine with Asp351 residue. Importantly,
showed favorable metabolic stability and good oral exposure.
exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 ...inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. ...The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
A series of 2,3,4,4a,10,10a-hexahydropyrano3,2-bchromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties ...were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2′ and P3 moieties were explored. A conformationally restricted P2′ methyl group provided inhibitors with excellent cell potency (37–137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1–40 at 60 mg/kg (PO).
Abstract
Hepatocellular carcinoma (HCC) is intrinsically resistant to conventional chemotherapies. Developing effective therapeutics becomes critical to tackle the unmet medical need. The fibroblast ...growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in liver development and homeostasis in adults. Deregulation of the FGF/FGFR signaling pathway through genetic modification or overexpression of the receptors (or their ligands) has been increasingly recognized in HCC. Accordingly, therapeutic intervention of the pathway has been extensively explored.
In this study, analysis of a panel of patient-derived xenograft (PDX) HCC models by Affymetrix human gene expression arrays revealed overexpression of FGFR1 in 13 out of 43 (30%) models. Antitumor activities of FGFR inhibitors, including lenvatinib, dovitinib, ENMD-2076, and LY2874455, were then tested in five models. Lenvatinib exhibited the most potent activity in all models, whereas LY2874455 failed to show the effect in one of models. IC50s for FGFR1 inhibition of ENMD-2076, lenvatinib, dovitinib and LY2874455 were 145 nM, 134.5 nM, 53.5 nM and 0.6 nM, respectively. In SNU-16 and NCI-H520 cell lines, IC50s of dovitinib, lenvatinib, ENMD-2076, and LY2874455 were 76/1355 nM, 94/4770 nM, 306/2280 nM, and 0.3/664 nM, respectively. Furthermore, analyses of PDX tissues by Affymetrix SNP Array 6.0 arrays revealed no amplification of FGFR1/2 genes in four models except for amplifications of FGFR3 gene in two models. Whole exome sequencing did not detect nonsynonymous genetic alterations, including SNPs and indels, in FGFR1/2 genes in these xenografts except for a few genetic variations in FGFR3/4 genes.
Overall, due to the multi-targeting mechanisms of these inhibitors, in vitro inhibitory effects of the compounds on FGFR1 enzyme and cell proliferation may not correlate with the in vivo anti-tumor activities. Overexpression of FGFR1 gene may serve as a predictive biomarker for therapeutic intervention of the FGF/FGFR pathway in HCC by using lenvatinib, dovitinib and ENMD-2076. Further studies are required to define additional biomarkers for LY2874455. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in a subset of HCC patients expressing a high level of FGFR1 gene.
Citation Format: Douglas D. Fang, Bin Zhang, Weiguo Xu, Kang Yan, Qingyang Gu, Qiang Xu, Yexiong Tan, Hongye Sun, Qin Luo, Weifeng Mao, Chiho Li, Jiangpeng Liao, Guibai Liang, Shu-Hui Chen, Chi-Chung Chan. Antitumor activities of FGFR inhibitors in FGFR1-overexpressing hepatocellular carcinoma patient-derived xenograft tumor models. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2014-2839
The interaction of a novel pesticide, NMD (spiro(2R,3R,4S)-4-benzyloxy-2,3-iso-propylidenedioxy-1-oxacyclopentane-5,5'-(2-nitromethylene-1,3-diazacyclohexane)), with bovine serum albumin (BSA) has ...been investigated by using absorption, fluorescence, and circular dichroism (CD) spectroscopy methods. Quenching of the fluorescence of BSA has been observed in the presence of NMD. The binding parameters were determined using Stern-Volmer equation. From the thermodynamic parameters calculated according to the van't Hoff equation, the enthalpy change ΔH, and entropy change ΔS were found to be -2.71 kJ mol-1 and 82.56 J mol-1 K-1, respectively. These values suggested that, apart from an initial hydrophobic association, the complex is held together by van der Waals interactions and hydrogen bonding. These results provided a quantitative understanding of the binding of NMD to BSA, which is important in understanding its toxicity in vertebrates.
PDF
