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1.
J Med Chem ; 62(22): 10108-10123, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31560541

ABSTRACT

Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/genetics , ErbB Receptors/metabolism , Exons , Humans , Male , Mice, Inbred ICR , Mice, Nude , Mutation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemistry , Rats , Receptor, ErbB-2 , Structure-Activity Relationship , Xenograft Model Antitumor Assays
2.
J Med Chem ; 56(13): 5247-60, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23808327

ABSTRACT

Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.


Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinase A/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase A/chemistry , Aurora Kinase A/metabolism , Body Weight/drug effects , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , Furans/chemistry , HCT116 Cells , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Ligands , Lipids/chemistry , Male , Mice , Mice, Nude , Models, Chemical , Models, Molecular , Molecular Structure , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Xenograft Model Antitumor Assays
3.
Proc Natl Acad Sci U S A ; 110(19): E1779-87, 2013 May 07.
Article in English | MEDLINE | ID: mdl-23610398

ABSTRACT

The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.


Subject(s)
Cell Cycle Proteins/metabolism , Centrosome/ultrastructure , Enzyme Inhibitors/pharmacology , Kinetochores/ultrastructure , Microtubules/metabolism , Neoplasm Proteins/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Aurora Kinase A , Aurora Kinases , Carcinoma, Hepatocellular/metabolism , Cell Cycle , Crystallography, X-Ray , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , Liver Neoplasms/metabolism , Male , Mice , Mice, Nude , Mitosis , Neoplasm Transplantation , Phosphorylation , Protein Structure, Tertiary
4.
ChemMedChem ; 8(1): 136-48, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23172777

ABSTRACT

We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC(50) values toward Aurora kinase A ranging from 33 nM to 10.5 µM. The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r(2) (CV) =0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R(2) (pred) =0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC(50) =43 nM; HCT-116 IC(50) =400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC(50) =25 nM; HCT-116 IC(50) =23 nM). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Protein Serine-Threonine Kinases/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Aurora Kinase A , Aurora Kinases , Humans , Male , Models, Molecular , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/metabolism , Quantitative Structure-Activity Relationship , Quinazolines/pharmacokinetics , Rats , Rats, Sprague-Dawley
5.
Anticancer Res ; 32(1): 147-51, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22213300

ABSTRACT

A high-throughput 32D(L858R/T790M) cell-based assay to identify inhibitors of the L858R/T790M mutant epidermal growth factor receptor (EGFR) pathway was established. After screening, ten hits from among 60,000 compounds in our in-house compound library were initially identified. In the secondary assays, one hit, 1-[2-(decyloxy)-2-oxoethyl]-3-methyl-2-[(4-methylphenoxy) methyl]-1H-benzimidazol-3-ium, was confirmed to directly inhibit the kinase activity of recombinant L858R/T790M EGFR and the phosphorylation of EGFR-L858R/T790M in gefitinib-resistant H1975 cells. Thus, this high-throughput assay system may be useful for identifying novel inhibitors which suppress mutant EGFR-T790M signalling and for overcoming T790M-mediated acquired resistance for future anticancer drug discovery.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Epidermal Growth Factor/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation/drug effects , Quinazolines/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gefitinib , High-Throughput Screening Assays , Humans , Lung Neoplasms/genetics , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects
6.
J Med Chem ; 53(20): 7316-26, 2010 Oct 28.
Article in English | MEDLINE | ID: mdl-20961149

ABSTRACT

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.


Subject(s)
Antineoplastic Agents/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung , Cell Line, Tumor , Drug Design , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , ErbB Receptors/genetics , Gefitinib , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Male , Mice , Mice, Nude , Mutation , Neoplasm Transplantation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous
7.
J Med Chem ; 53(13): 4980-8, 2010 Jul 08.
Article in English | MEDLINE | ID: mdl-20550212

ABSTRACT

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.


Subject(s)
Carcinoma, Non-Small-Cell Lung/enzymology , ErbB Receptors/antagonists & inhibitors , Furans/chemistry , Lung Neoplasms/enzymology , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinases , Blotting, Western , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , ErbB Receptors/metabolism , Furans/chemical synthesis , Furans/pharmacology , Humans , Inhibitory Concentration 50 , Lung Neoplasms/drug therapy , Magnetic Resonance Spectroscopy , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Spectrometry, Mass, Fast Atom Bombardment
8.
ChemMedChem ; 5(2): 255-67, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20039358

ABSTRACT

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.


Subject(s)
Furans/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Aurora Kinases , Binding Sites , Crystallography, X-Ray , High-Throughput Screening Assays , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship
9.
J Med Chem ; 52(15): 4941-5, 2009 Aug 13.
Article in English | MEDLINE | ID: mdl-19586033

ABSTRACT

BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.


Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Colchicine/metabolism , Drug Design , Humans , Indoles/metabolism , Indoles/pharmacokinetics , Indoles/pharmacology , Mice , Rats , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology
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