Abstract:
:As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kong X,Pan P,Sun H,Xia H,Wang X,Li Y,Hou Tdoi
10.1021/acs.jmedchem.9b00446subject
Has Abstractpub_date
2019-12-26 00:00:00pages
10927-10954issue
24eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章,评审abstract::Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and bio...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901561u
更新日期:2010-03-11 00:00:00
abstract::A novel series of diaminoanthraquinones was discovered initially as protein kinase C inhibitors with IC50s in the 50-100 microM range. They exhibited potent tumor cell growth inhibitory activity in vitro without cross resistance to adriamycin. Further evaluation of two of the most active compounds NSC 639365 (3) and N...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00101a001
更新日期:1992-11-13 00:00:00
abstract::An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm7012979
更新日期:2009-02-12 00:00:00
abstract::Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is overstimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the C...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.7b00873
更新日期:2018-07-12 00:00:00
abstract::Human G93A-superoxide dismutase-1 (G93AhSOD1) mutation causes amyotrophic lateral sclerosis (ALS) in rodents and humans. Recent observations indicate gain of interaction of G93AhSOD1 with cytosolic malate dehydrogenase (MDH1) and subsequent impairment in the malate aspartate shuttle which is vital to neurons. Using fl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900631m
更新日期:2009-09-10 00:00:00
abstract::The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indica...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300414b
更新日期:2012-09-13 00:00:00
abstract::Enantiomerically pure (+)- and (-)-carbocyclic thymidine, (-)-carbocyclic 3'-epi-thymidine, (+)-carbocyclic 3'-deoxy-3'-azidothymidine, (+)-carbocyclic 2,3'-O-anhydrothymidine, (+)-carbocyclic 3'-O,6'-methylenethymidine, and (+)-(6'S)-carbocyclic 6'-methylthymidine were synthesized in a stereospecific manner from comm...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00167a011
更新日期:1990-05-01 00:00:00
abstract::In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980656r
更新日期:1999-04-22 00:00:00
abstract::Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100165w
更新日期:2010-05-27 00:00:00
abstract::Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301824k
更新日期:2013-04-25 00:00:00
abstract::The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0211218
更新日期:2003-05-22 00:00:00
abstract::Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01395
更新日期:2017-11-09 00:00:00
abstract::c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm502018y
更新日期:2015-03-12 00:00:00
abstract::The nature of the carbonyl and nitrogen substituents of hydroxamic acids has a major influence on the biological profile of these compounds. Hydroxamates with small groups such as methyl appended to the carbonyl and relatively large nitrogen substituents generally have longer duration in vivo, produce greater plasma c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00118a016
更新日期:1988-10-01 00:00:00
abstract::New and greatly improved preparations of the 12alpha,1'beta- (5) and 12beta,1'beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12alpha-epimer 5...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm001061a
更新日期:2001-04-26 00:00:00
abstract::Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Lig...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900838g
更新日期:2010-01-28 00:00:00
abstract::A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050499d
更新日期:2005-08-11 00:00:00
abstract::Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC delta C1b domain, we have discovered conveni...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900229p
更新日期:2009-07-09 00:00:00
abstract::The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501266w
更新日期:2014-12-11 00:00:00
abstract::A series of pepstatin analogues having structural variations in the P2', P1', and P2 positions have been synthesized and tested for inhibition of porcine pepsin. The standard peptide for this study was Iva-Sta-Val-Ala-Iaa. Structural variations in the P2' and P1' positions have relatively little effect on Ki; however,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00360a022
更新日期:1983-06-01 00:00:00
abstract::A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00375a017
更新日期:1984-09-01 00:00:00
abstract::G-Quadruplexes, noncanonical nucleic acid structures, act as silencers in the promoter regions of human genes; putative G-quadruplex forming sequences are also present in promoters of other mammals, yeasts, and prokaryotes. Here we show that also the HIV-1 LTR promoter exploits G-quadruplex-mediated transcriptional re...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400914r
更新日期:2013-08-22 00:00:00
abstract::Overexpression of the HER2 receptor is observed in about 30% of breast and ovarian cancers and is often associated with an unfavorable prognosis. We have recently designed an anti-HER2 peptide (AHNP) based on the structure of the CDR-H3 loop of the anti-HER2 rhumAb 4D5 and showed that this peptide can mimic some funct...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000527m
更新日期:2001-08-02 00:00:00
abstract::Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050021+
更新日期:2005-06-16 00:00:00
abstract::New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00035a012
更新日期:1994-04-29 00:00:00
abstract::Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resist...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00347
更新日期:2020-07-23 00:00:00
abstract::1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were int...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00225a017
更新日期:1976-03-01 00:00:00
abstract::Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900093d
更新日期:2009-04-09 00:00:00
abstract::A number of 7-benzoylbenzofuran-5-ylacetic acids and 7-benzoylbenzothiophene-5-ylacetic acids were synthesized. The compounds were generally only 1/2 to 3 times as potent as phenylbutazone in the rat paw edema antiinflammatory assay. However, they show greater activity as analgetic agents. The most active compound is ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00161a030
更新日期:1986-11-01 00:00:00
abstract::FK506-binding proteins (FKBPs) are evolutionarily conserved proteins that display peptidyl-prolyl isomerase activities and act as coreceptors for immunosuppressants. Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs can enhance infectivity. However, developing druglike ligands for FKBPs or Mips has proven ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00137
更新日期:2018-04-26 00:00:00