Xiaolun Wang

Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of SNAr Reactions of Electron-Deficient Polyfluoroarenes

It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.

Discovery of highly potent and selective type I B-Raf kinase inhibitors

A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.

Discovery of indazoles as inhibitors of Tpl2 kinase.

Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay.

Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity.

Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.

Structure-based design of isoindoline-1,3-diones and 2,3-dihydrophthalazine-1,4-diones as novel B-Raf inhibitors.

Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified.

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure.

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

Correction to “Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure”

[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].

Abstract A85: Discovery of highly potent and selective B‐Raf Kinase inhibitors

B‐Raf kinase, a serine/threonine protein kinase, is a component of RAS‐Raf‐MEK‐ERK signaling pathway and plays a central role in cell growth and survival. B‐Raf mutations have been found in about 8% of all cancers with the highest incidence in melanomas (66%). Thus a potent Raf inhibitor could have a significant impact in treating cancers that are dependent on this pathway for survival and proliferation signaling. As part of our program to prepare potent and structurally novel B‐Raf kinase inhibitors, we designed a series of substituted pyrazolo[1,5‐ ]pyrimidines. Molecular modeling studies were utilized to validate the preparation of this series, as well as to optimize analogs to ultimately provide B‐Raf inhibitors with subnanomolar IC50s. The modeling result also suggested these compounds bind to the active conformation of B‐Raf. These pyrazolo[1,5‐ ]pyrimidine derivatives have moderate selectivity for B‐Raf vs. C‐Raf. Selected examples were screened for inhibition of a panel of 24 kinases and found to be highly selective. In addition to their enzymatic potency, the cell antiproliferative activities of these inhibitor were evaluated in B‐Raf mutant cell lines (A375,WM266‐4) and a cell line with wild type B‐Raf (Caco‐2). Selective inhibition of the B‐Raf mutant cell lines with IC50 values less than 10 nM was observed for the most potent compounds. Finally, protein immunoblot analyses confirmed the inhibition of this MAPK signaling pathway by these analogs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A85.