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1.
Bioorg Med Chem Lett ; 59: 128576, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35065235

ABSTRACT

Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.


Subject(s)
Enzyme Inhibitors/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Lactams/pharmacology , Animals , Cell Line , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , L-Lactate Dehydrogenase/metabolism , Lactams/chemistry , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Structure-Activity Relationship
2.
ACS Med Chem Lett ; 7(10): 896-901, 2016 Oct 13.
Article in English | MEDLINE | ID: mdl-27774125

ABSTRACT

A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 µM lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 µM) that also possessed good exposure when dosed orally to mice.

3.
Nat Chem Biol ; 12(10): 779-86, 2016 10.
Article in English | MEDLINE | ID: mdl-27479743

ABSTRACT

Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.


Subject(s)
Cell Plasticity/drug effects , Enzyme Inhibitors/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Pyridones/pharmacology , Thiophenes/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , L-Lactate Dehydrogenase/metabolism , Models, Molecular , Molecular Structure , Pyridones/chemistry , Structure-Activity Relationship , Thiophenes/chemistry
4.
J Med Chem ; 59(12): 5650-60, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27227380

ABSTRACT

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridones/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridones/chemical synthesis , Pyridones/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 25(15): 2907-12, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26048793

ABSTRACT

The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.


Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Cell Line , Cells, Cultured , Drug Discovery , HEK293 Cells , Humans , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Interleukin-17/immunology , Liver/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , Pyridines/metabolism , Pyridines/pharmacokinetics , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 25(1): 75-82, 2015 Jan 01.
Article in English | MEDLINE | ID: mdl-25466195

ABSTRACT

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4­10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.


Subject(s)
Enzyme Inhibitors/chemical synthesis , L-Lactate Dehydrogenase/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , L-Lactate Dehydrogenase/metabolism , Madin Darby Canine Kidney Cells
7.
Bioorg Med Chem Lett ; 24(24): 5683-5687, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25467161

ABSTRACT

A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50=30 nM).


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Pyrones/chemical synthesis , Pyrones/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , L-Lactate Dehydrogenase/metabolism , Models, Molecular , Molecular Structure , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 24(16): 3764-71, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-25037916

ABSTRACT

A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 µM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 µM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).


Subject(s)
Cyclohexanones/pharmacology , Enzyme Inhibitors/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Sulfhydryl Compounds/pharmacology , Administration, Oral , Animals , Cyclohexanones/administration & dosage , Cyclohexanones/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , High-Throughput Screening Assays , Humans , L-Lactate Dehydrogenase/metabolism , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Sulfhydryl Compounds/administration & dosage , Sulfhydryl Compounds/chemistry
9.
J Immunol ; 191(5): 2205-16, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23894201

ABSTRACT

TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.


Subject(s)
Cytokines/immunology , Protein Kinase Inhibitors/pharmacology , Signal Transduction/immunology , TYK2 Kinase/immunology , TYK2 Kinase/metabolism , Animals , Cytokines/metabolism , Humans , Immunoblotting , Interleukin-12/immunology , Interleukin-12/metabolism , Interleukin-23/immunology , Interleukin-23/metabolism , Mice , Signal Transduction/drug effects
10.
J Med Chem ; 55(22): 10090-107, 2012 Nov 26.
Article in English | MEDLINE | ID: mdl-23061660

ABSTRACT

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.


Subject(s)
Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Female , Humans , Janus Kinase 2/metabolism , Mice , Mice, SCID , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemistry , STAT5 Transcription Factor/metabolism , Structure-Activity Relationship , Tissue Distribution
11.
J Med Chem ; 51(15): 4465-75, 2008 Aug 14.
Article in English | MEDLINE | ID: mdl-18630890

ABSTRACT

Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Humans , Lactams/chemistry , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/metabolism , Rats
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