ABSTRACT
Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Animals , Cells, Cultured , Endothelial Cells , Humans , Hypertension, Pulmonary/drug therapy , Pulmonary ArteryABSTRACT
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
Subject(s)
Enzyme Activators/chemistry , Glucokinase/chemistry , Hypoglycemic Agents/chemistry , Animals , Binding Sites , Blood Glucose/analysis , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Drug Design , Drug Evaluation, Preclinical , Enzyme Activators/metabolism , Enzyme Activators/therapeutic use , Glucokinase/metabolism , Glucose Tolerance Test , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/therapeutic use , Kinetics , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/metabolismABSTRACT
E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.
Subject(s)
Indoles/chemistry , Intracellular Signaling Peptides and Proteins/chemistry , RNA-Binding Proteins/chemistry , Sulfonamides/chemistry , Binding Sites , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Kinetics , Molecular Docking Simulation , Protein Binding , RNA-Binding Proteins/metabolismABSTRACT
Most published studies addressing the role of hypoxia inducible factors (HIFs) in hypoxia-induced pulmonary hypertension development employ models that may not recapitulate the clinical setting, including the use of animals with pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Furthermore, critical questions including how and when HIF signalling contributes to hypoxia-induced pulmonary hypertension remain unanswered.Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4â days) or chronic (4-5â weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion).Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5â weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2-ASO (but not Hif1-ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4-5â weeks of hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4â days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5â weeks of hypoxia. In vitro, HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice.Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Hypertension, Pulmonary/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Pulmonary Artery/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Endothelial Cells/pathology , Female , Gene Expression Regulation , Hypertension, Pulmonary/pathology , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/pathology , Hypoxia/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Pulmonary Artery/cytology , Rats , Rats, Sprague-Dawley , Signal Transduction , Vascular RemodelingABSTRACT
The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.
Subject(s)
Antineoplastic Agents/therapeutic use , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/drug therapy , Indans/therapeutic use , Kidney Neoplasms/drug therapy , Sulfones/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinoma, Renal Cell/metabolism , Dogs , Dose-Response Relationship, Drug , Female , Haplorhini , Humans , Indans/chemical synthesis , Indans/pharmacology , Kidney Neoplasms/metabolism , Mice , Mice, SCID , Rats , Sulfones/chemical synthesis , Sulfones/pharmacology , Treatment Outcome , Xenograft Model Antitumor Assays/methodsABSTRACT
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n â π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/pathology , Drug Design , Indans/chemistry , Indans/pharmacology , Kidney Neoplasms/pathology , Sulfones/chemistry , Sulfones/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Basic Helix-Loop-Helix Transcription Factors/chemistry , Cell Line, Tumor , Dogs , Indans/pharmacokinetics , Mice , Models, Molecular , Protein Conformation , Rats , Structure-Activity Relationship , Sulfones/pharmacokinetics , Tissue DistributionABSTRACT
Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/drug therapy , Indans/administration & dosage , Kidney Neoplasms/drug therapy , Sulfones/administration & dosage , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/pathology , Dose-Response Relationship, Drug , Female , Humans , Indans/adverse effects , Indans/blood , Kidney Neoplasms/blood , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Sulfones/adverse effects , Sulfones/bloodABSTRACT
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1ß. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Animals , Antineoplastic Agents/chemistry , Calorimetry , Cell Line, Tumor , Crystallography, X-Ray , Humans , Immunohistochemistry , Immunoprecipitation , Mice , Mice, SCID , Polymerase Chain Reaction , Xenograft Model Antitumor AssaysABSTRACT
Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Indans/pharmacology , Indans/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Sulfones/pharmacology , Sulfones/therapeutic use , Animals , Biomarkers, Pharmacological , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Cell Line, Tumor , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Mice , Models, Biological , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Transcription, Genetic/drug effects , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Indans/pharmacology , Indans/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Sulfones/pharmacology , Sulfones/therapeutic use , Animals , Aryl Hydrocarbon Receptor Nuclear Translocator/genetics , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Binding Sites , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , Drug Resistance, Neoplasm/drug effects , Erythropoietin/antagonists & inhibitors , Erythropoietin/blood , Female , Gene Expression Regulation, Neoplastic , Humans , Indans/administration & dosage , Indoles/pharmacology , Indoles/therapeutic use , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Targeted Therapy , Mutation , Pyrroles/pharmacology , Pyrroles/therapeutic use , Reproducibility of Results , Sulfones/administration & dosage , Sunitinib , Xenograft Model Antitumor AssaysABSTRACT
The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.
Subject(s)
Adenosine Triphosphate/metabolism , Binding, Competitive , Drug Discovery , Piperazines/metabolism , Piperazines/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/metabolism , Pyrimidines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Piperazines/chemistry , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/chemistry , Pyrimidines/chemistry , Substrate SpecificityABSTRACT
We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Spiro Compounds/chemistry , Sulfonamides/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Cyclic AMP-Dependent Protein Kinases/metabolism , Drug Evaluation, Preclinical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Pyridines/chemical synthesis , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line , Cell Line, Tumor , Cell Membrane Permeability , Cell Survival/drug effects , Drug Stability , Hepatocytes/metabolism , Humans , In Vitro Techniques , Mice , Phosphorylation , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Solubility , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specificity kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. Representative examples of both ATP competitive and non-competitive inhibitors as well as natural product based inhibitors will be discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Biological Factors , Enzyme Inhibitors/chemistry , Humans , Neoplasms/physiopathology , Signal Transduction/drug effectsABSTRACT
The synthesis of allenic acids and esters and their conversion to butenolides has been examined in some detail. Racemic butenolides 10 are efficiently prepared from the esters 8 through treatment with BCl(3) and exposure of the derived acid 9 to catalytic AgNO(3) in acetone. Conversion of the enantioenriched allenylstannane (S)-17 to the acid 18 through lithiation and subsequent carboxylation with CO(2) afforded racemic product. The enantioenriched propargylic mesylates 16 and 22 afforded the allenic esters 19 and 23 with inversion of configuration through treatment with Pd(Ph(3)P)(4), CO, and the appropriate alcohol in THF. These reactions proceeded with ca. 10% or less of racemization. The allenic esters 23 yielded the iodobutenolides 24 by reaction with IBr. Hydrogenolysis to the butenolide 25 was achieved with Pd(PPh(3))(4) and Bu(3)SnH. Alternatively, the allenic acids 27 could be prepared directly from mesylates 22 with Pd(PPh(3))(4) and CO in aqueous THF. Cyclization to the butenolides 25 was achieved, as before, with catalytic AgNO(3).