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1.
Bioorg Med Chem ; 49: 116437, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34600239

ABSTRACT

AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.


Subject(s)
Drug Discovery , Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Axl Receptor Tyrosine Kinase
2.
Angew Chem Int Ed Engl ; 59(32): 13295-13304, 2020 08 03.
Article in English | MEDLINE | ID: mdl-32337801

ABSTRACT

The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Bacterial Proton-Translocating ATPases/antagonists & inhibitors , Diarylquinolines/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Benzamides/toxicity , Drug Synergism , Embryonic Stem Cells/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Humans , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/toxicity , Structure-Activity Relationship
3.
Eur J Med Chem ; 106: 144-56, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26544629

ABSTRACT

Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Pyridones/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/metabolism , Biological Availability , Dose-Response Relationship, Drug , Drug Stability , Humans , Mice , Microbial Sensitivity Tests , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Pyridones/chemistry , Pyridones/metabolism , Rats , Structure-Activity Relationship
4.
Sci Transl Med ; 7(269): 269ra3, 2015 Jan 07.
Article in English | MEDLINE | ID: mdl-25568071

ABSTRACT

New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Oxidoreductases/antagonists & inhibitors , Animals , Antitubercular Agents/chemistry , Bacterial Proteins/metabolism , Biophysical Phenomena/drug effects , Crystallography, X-Ray , Disease Models, Animal , Drug Resistance, Multiple, Bacterial/drug effects , Enzyme Inhibitors/chemistry , Mice, Inbred BALB C , Models, Molecular , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/isolation & purification , Oxidoreductases/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Reproducibility of Results , Sequence Analysis, DNA , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology
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