Minhang Xin

Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors.

A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.

The discovery of novel N-(2-pyrimidinylamino) benzamide derivatives as potent hedgehog signaling pathway inhibitors.

Hedgehog signaling pathway inhibitors are emerging as new therapeutic intervention against cancer. A novel series of N-(2-pyrimidinylamino) benzamide derivatives as hedgehog signaling pathway inhibitors were designed and synthesized. Most compounds presented significant inhibitory effect on hedgehog signaling pathway, among which 21 compounds exhibited more potent than vismodegib. Furthermore, compound 6a showed moderate pharmacokinetic properties in vivo, representing a promising lead compound for further exploration.

Discovery of novel Bruton’s tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.

Hedgehog inhibitors: a patent review (2013 – present)

Introduction: The hedgehog (Hh) signaling pathway is an important signaling pathway, playing a critical role in regulation of cell growth, development, metastasis and angiogenesis. Aberrant activation of this pathway has been linked to the development of several human tumor types, which makes it an attractive target for cancer treatment. Now many efforts in both industry and academia have been made to explore small molecular Hh inhibitors as anticancer agents. Areas covered: This review aims to provide an overview of recent patents (2013 – present) in the discovery, research and development of Hh inhibitors. Expert opinion: Hh signaling pathway inhibitors attract much interest for their therapeutic potential in the treatment of a variety of human cancers. In 2012, vismodegib was approved by the FDA as a smoothened inhibitor for locally advanced or metastatic basal cell carcinoma treatment, and presently, it is ongoing clinical trials for validating its use in other tumor types. It is clear that Hh inhibitors may provide a promising clinical benefit in treating tumors involving active Hh signaling pathway with a mutation-driven mechanism. However, the efficacy of Hh inhibitors on other human tumor types is still needed to further identify.

Synthesis and evaluation of 4-(2-pyrimidinylamino) benzamides inhibitors of hedgehog signaling pathway.

A novel series of hedgehog signaling pathway inhibitors has been designed based on the 4-(2-pyrimidinylamino) benzamides scaffold. The synthesis and SAR of these compounds are described. Optimization leads to the identification of compound 3c, a potent and orally available agent with improved physicochemical and pharmacokinetic properties.

Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo

In the present study, a series of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, synthesized and characterized. The antiproliferative activities of the synthesized compounds were evaluated against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 μM were further evaluated against U-87 MG and A549 cell lines. Among these evaluated compounds, compound T10 displayed a remarkable antiproliferative effect in vitro. The hoechst staining assay showed that compound T10 caused morphological changes. The cell cycle and apoptosis assay further indicated that compound T10 can arrest HCT-116 cells in G2/M and G0/G1 phase and induce apoptosis. PI3K enzyme assays indicated that compounds T7 and T10 selectively inhibit PI3Kα. A Western bolt assay further suggested that compound T10 can block the PI3K/Akt/mTOR pathway. Moreover, compound T10 inhibited tumor growth on a mice S180 homograft model. These findings directly identify m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as novel anticancer agents.

Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors.

A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.

Design, synthesis, and biological study of 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine derivatives as novel hedgehog signaling pathway inhibitors

A novel series of hedgehog signaling pathway inhibitors were designed by replacing the pyrimidine nucleus of our earlier reported compounds with 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine scaffold. Among this new class of hedgehog signaling pathway inhibitors, compounds 14 and 18 exhibited promising potency in vitro compared to GDC-0449. Compound 18 was advanced to profile its pharmacokinetic characteristics, and showed moderate pharmacokinetic properties in vivo, indicating that the 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine skeleton is a promising scaffold for further exploration as hedgehog signaling pathway inhibitors.

Synthesis and antitumor activity evaluation of 4,6-disubstituted quinazoline derivatives as novel PI3K inhibitors

A series of 4,6-disubstituted quinazoline derivatives as potential PI3K inhibitors were designed and synthesized. All compounds exhibited significant anti-proliferative activities against HCT-116 and MCF-7 cell lines, and compounds A7, A9, and A11 displayed the most potent anti-proliferative activity against the HCT-116. Further PI3K inhibitory activity evaluation showed that compound A7 displayed high potency against PI3K enzymes. The in vivo anti-tumor study showed compound A7 can efficaciously inhibit tumor growth in a mice S-180 model. These results suggest that our designed compounds can serve as potent PI3K inhibitors and effective antitumor agents.

Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety.

In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.