Recent Progress in the Development of Small Molecule c-Met Inhibitors

2019 ◽  
Vol 19 (15) ◽  
pp. 1276-1288 ◽  
Author(s):  
Peng-Cheng Lv ◽  
Yu-Shun Yang ◽  
Zhong-Chang Wang
Keyword(s):  
Small Molecule ◽  
Rational Design ◽  
Antitumor Agents ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Human Tumor ◽  
Design Synthesis ◽  
Relationship Analysis ◽  
Tumor Types ◽  
Hepatocyte Growth

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.

scholarly journals Use of 2-aminoprop-1-ene-1,1,3-tricarbonitrile for the synthesis of tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives with potential antitumor activities

2011 ◽  
Vol 61 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Rafat Mohareb ◽  
Hosam Moustafa
Keyword(s):  
Cell Lines ◽  
Antitumor Agents ◽  
Human Tumor ◽  
Breast Adenocarcinoma ◽  
Inhibitory Effects ◽  
Antitumor Activities ◽  
Chemical Reagents ◽  
Tumor Types ◽  
Potential Antitumor

Use of 2-aminoprop-1-ene-1,1,3-tricarbonitrile for the synthesis of tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives with potential antitumor activities The aim of the work was to synthesize heterocyclic compounds from 2-aminoprop-1-ene-1,1,3-tricarbonitrile and to study their antitumor activities. The title reagent reacted with cyclohexanone to give the ethylidene derivative 2. The reactivity of the latter product towards different chemical reagents was studied to give tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives. The newly synthesized products were screened as antitumor agents on the in vitro growth of three human tumor cell lines representing different tumor types, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). It was found that some of these compounds showed inhibitory effects on the three cell lines, indicating their potential use in the development of oncology products.

KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid Tumors

2005 ◽  
Vol 23 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Harri Sihto ◽  
Maarit Sarlomo-Rikala ◽  
Olli Tynninen ◽  
Minna Tanner ◽  
Leif C. Andersson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Platelet Derived Growth Factor ◽  
Wild Type ◽  
Pdgfra Gene ◽  
Factor Receptor Alpha ◽  
Kit Gene ◽  
Histologic Types ◽  
Tumor Types

Purpose Mutated KIT and platelet-derived growth factor receptor alpha (PDGFRα) tyrosine kinases are the principal targets for imatinib mesylate in the treatment of gastrointestinal stromal tumors (GISTs). The frequency of activating KIT and PDGFRA gene mutations in most other histologic types of human cancer is not known. Materials and Methods KIT exons 9, 11, 13, and 17 and PDGFRA exons 11 and 17 of 334 human cancers were screened for mutations using sensitive denaturing high-performance liquid chromatography (DHPLC). In addition, all KIT exons from 9 to 21 of 115 tumors were screened. Thirty-two histologic tumor types were examined. Samples with abnormal findings in DHLPC were sequenced. Immunostaining for the KIT protein (CD117) was performed in 322 (96.4%) of the 334 cases. Results Of the 3,039 exons screened, only 17 had mutation. All 17 cases with either mutated KIT (n = 15) or PDGFRA (n = 2) were histologically GIST tumors, whereas none of the other histologic types of cancer (n = 316) harbored KIT or PDGFRA mutation. KIT immunostaining was rarely positive except in GISTs (18 of 18), small-cell lung cancer (10 of 30; 33%), and testicular teratocarcinoma (four of 17; 24%). Wild-type KIT gene amplification or chromosome 4 aneuploidy was common (seven of 12) in non-GIST tumors with strong KIT protein expression when studied with fluorescence in situ hybridization. Conclusion Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.

scholarly journals Targeting the Hepatocyte Growth Factor–cMET Axis in Cancer Therapy

2012 ◽  
Vol 30 (26) ◽  
pp. 3287-3296 ◽  
Author(s):  
George R. Blumenschein ◽  
Gordon B. Mills ◽  
Ana M. Gonzalez-Angulo
Keyword(s):  
Growth Factor ◽  
Cancer Therapy ◽  
Hepatocyte Growth Factor ◽  
Gene Amplification ◽  
Growth Factor Receptor ◽  
Lung Cancers ◽  
Promote Cell Proliferation ◽  
Tissue Repair And Regeneration ◽  
Tumor Types ◽  
Hepatocyte Growth

The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non–small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.

The outcomes of small-molecule kinase inhibitors and the role of ROCK2 as a molecular target for the treatment of Alzheimer's disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Heber Victor Tolomeu ◽  
Carlos Alberto Manssour Fraga
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Active Site ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Structural Characteristics ◽  
Structural Features ◽  
Relationship Analysis ◽  
Promising Target

Background: Alzheimer's disease is rapidly becoming a major threat to public health, with an increasing number of individuals affected as the world's population ages. In this sense, studies have been carried out aiming at the identification of new small-molecule kinase inhibitors useful for the treatment of Alzheimer's disease. Objective: In the present study, we investigated the compounds developed as inhibitors of different protein kinases associated with the pathogenesis of Alzheimer's disease. Methods: The applied methodology was the use of the Clarivate Analytics Integrity and ClinicalTrials.com databases. Moreover, we highlight ROCK2 as a promising target despite being little studied for this purpose. A careful structure-activity relationship analysis of the ROCK2 inhibitors was performed to identify important structural features and fragments for the interaction with the kinase active site, aiming to rationally design novel potent and selective inhibitors. Results: We were able to notice some structural characteristics that could serve as the basis to better guide the rational design of new ROCK2 inhibitors as well as some more in-depth characteristics regarding the topology of the active site of both isoforms of these enzymes, thereby identifying differences that could lead to planning more selective compounds. Conclusion: We hope that this work can be useful to update researchers working in this area, enabling the emergence of new ideas and a greater direction of efforts for designing new ROCK2 inhibitors to identify new therapeutic alternatives for Alzheimer's disease.

Rational design, synthesis and biological evaluation of thiadiazinoacridines: A new class of antitumor agents

2003 ◽  
Vol 11 (3) ◽  
pp. 399-405 ◽  
Author(s):  
Ippolito Antonini ◽  
Paolo Polucci ◽  
Amelia Magnano ◽  
Diego Cacciamani ◽  
Marek T Konieczny ◽  
...  
Keyword(s):  
Rational Design ◽  
Antitumor Agents ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
New Class ◽  
Synthesis And Biological Evaluation

scholarly journals MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

2019 ◽  
Vol 116 (15) ◽  
pp. 7533-7542 ◽  
Author(s):  
Jessica B. Casaletto ◽  
Melissa L. Geddie ◽  
Adnan O. Abu-Yousif ◽  
Kristina Masson ◽  
Aaron Fulgham ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Bispecific Antibody ◽  
Human Tumor ◽  
Clinical Development ◽  
Inhibition Of Proliferation ◽  
Wide Range ◽  
Inhibition Of Tumor Growth ◽  
Xenograft Models ◽  
Tumor Types ◽  
Hepatocyte Growth

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.

Cytotoxicity and Molecular Targeting Study of Novel 2-Chloro-3- substituted Quinoline Derivatives as Antitumor Agents

2019 ◽  
Vol 16 (3) ◽  
pp. 273-283 ◽  
Author(s):  
Mohammed A.M. Massoud ◽  
Magda A. El-Sayed ◽  
Waleed A. Bayoumi ◽  
Basem Mansour
Keyword(s):  
Cell Lines ◽  
Antitumor Agents ◽  
Growth Factor Receptor ◽  
Human Tumor ◽  
Quinoline Derivatives ◽  
Human Tumor Cell Lines ◽  
Topoisomerase 1 ◽  
Analysis Of Results ◽  
Epidermal Growth

Background: Quinoline scaffold acts as “privileged structure” for anticancer drug design. Certain derivatives showed good results through different mechanisms as topoisomerase 1 and kinase inhibition. </P><P> Methods: A new series of 2-chloro-3-(2-amino-3-cyano-4H-chromene, 4H-pyranyl and fused 1- cyclohexen-4-yl)quinoline structures (3-5, 6 and 7) were designed, synthesized, and evaluated for their in vitro antitumor activity. All compounds were tested by MTT assay against a panel of four different human tumor cell lines. The inhibitory activity of selected compounds was assessed on topoisomerase 1 and epidermal growth factor receptor tyrosine kinase via ELISA. In addition, compounds 7b and 3a were docked into the X-ray crystal structure of Topo 1 and EGFR enzymes, respectively to explain the molecular basis of the potent activity. </P><P> Results: Compounds 3a, 3b and 7b showed characteristic efficacy profile. 7b showed the best cytotoxic activity on all types of tested cell lines with IC50 range (15.8&#177;1.30 to 28.2&#177;3.37 &#181;M), relative to 5-fluoruracil of IC50 range (40.7&#177;2.46 to 63.8&#177;2.69 &#181;M). Via ELISA, 7b and 3a showed characteristic inhibition profile on Topo 1 and EGFR-TK respectively. In addition, 7b has scored binding energy (101.61 kcal/mol) and six hydrogen bonds with amino acids conserved residues in the enzyme pocket. </P><P> Conclusion: Analysis of results revealed that compounds 7a and 7b mainly were Topo 1 inhibitors while 3a was mainly EGFR inhibitor. This property may be exploited to design future quinoline derivatives as antitumor agents with enhanced selectivity towards either of the two molecular targets.

scholarly journals New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation

2021 ◽  
Vol 71 (4) ◽  
pp. 545-565
Author(s):  
Dima A. Sabbah ◽  
Bara’a A. Al-Azaideh ◽  
Wamidh H. Talib ◽  
Rima Hajjo ◽  
Kamal Sweidan ◽  
...  
Keyword(s):  
Rational Design ◽  
Antitumor Agents ◽  
Human Colon ◽  
Ionization Potentials ◽  
Tryptophan Residue ◽  
Design Synthesis ◽  
Hct 116 ◽  
Phosphoinositide 3 Kinase ◽  
Proliferation Assays

Abstract Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N’-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.

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