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1.
J Med Chem ; 67(11): 9759-9771, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38820338

ABSTRACT

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.


Subject(s)
Protein Kinase Inhibitors , Receptor, ErbB-2 , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Animals , Drug Discovery , Mutation , Cell Line, Tumor , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Rats , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism
2.
Cancer Discov ; 13(8): 1789-1801, 2023 08 04.
Article in English | MEDLINE | ID: mdl-37269335

ABSTRACT

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.


Subject(s)
Lung Neoplasms , Protein-Tyrosine Kinases , Humans , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Oncogenes , Patient-Centered Care
3.
Bioorg Med Chem Lett ; 24(8): 1923-7, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24675381

ABSTRACT

Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.


Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quinazolines/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
4.
Future Med Chem ; 5(17): 2037-56, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24215345

ABSTRACT

BACKGROUND: Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis. RESULTS: Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole. CONCLUSION: The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.


Subject(s)
Oxazoles/chemistry , Oxazoles/pharmacology , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/pharmacology , Animals , Humans , Hydrogen Bonding , Microsomes/metabolism , Models, Molecular , Oxazoles/metabolism , Oxazoles/pharmacokinetics , Purinergic P2Y Receptor Antagonists/metabolism , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 23(21): 5896-9, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24042006

ABSTRACT

This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.


Subject(s)
Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Animals , Caco-2 Cells , Drug Design , Humans , Mice , Molecular Docking Simulation , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Purines/pharmacokinetics , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 22(19): 6237-41, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22954737

ABSTRACT

Cell potent inhibitors of B-Raf(V600E) that bind to the kinase in the DFG-out conformation are reported. These compounds utilize the hinge-binding group and lipophilic linker from a previously disclosed series of B-Raf(V600E) inhibitors that bind to the kinase in an atypical DFG-in, αC-helix-out conformation. This new series demonstrates that DFG-out kinase inhibitors can be rationally designed from related inhibitors which utilize an unconventional binding mode. Kinase selectivity profiles are compared. The pattern of kinase selectivity was found to be determined by the feature of the inhibitor which extends into the back pocket of the kinase and leads to the kinase conformation, rather than by the hinge-binding group or other minor modifications.


Subject(s)
Drug Design , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Stability , Humans , Mice , Microsomes/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 22(10): 3387-91, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22534450

ABSTRACT

Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.


Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrimidinones/pharmacology , Administration, Oral , Biological Availability , Crystallography, X-Ray , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics
8.
J Med Chem ; 55(6): 2869-81, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-22335519

ABSTRACT

Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.


Subject(s)
Aminopyridines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Mice , Models, Molecular , Molecular Structure , Neoplasm Transplantation , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Solubility , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Transplantation, Heterologous
9.
Bioorg Med Chem Lett ; 22(2): 1165-8, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22196124

ABSTRACT

Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties.


Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Chemistry, Physical , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 21(18): 5533-7, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21802293

ABSTRACT

Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyridines/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity Relationship
12.
J Med Chem ; 54(8): 2839-63, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21417219

ABSTRACT

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.


Subject(s)
Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Drug Discovery , Endopeptidases/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Cyclopropanes/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Knockout , Models, Molecular , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 21(4): 1243-7, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21251822

ABSTRACT

The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.


Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Amino Acid Substitution , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indazoles/chemistry , Mice , Microsomes, Liver/metabolism , Mutation , Oximes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemistry , Structure-Activity Relationship
15.
ACS Med Chem Lett ; 2(5): 342-7, 2011 May 12.
Article in English | MEDLINE | ID: mdl-24900315

ABSTRACT

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

17.
Bioorg Med Chem Lett ; 19(6): 1575-80, 2009 Mar 15.
Article in English | MEDLINE | ID: mdl-19243944

ABSTRACT

A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.


Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , ADAMTS5 Protein , Carboxylic Acids/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Osteoarthritis/drug therapy , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship
18.
J Med Chem ; 52(6): 1731-43, 2009 Mar 26.
Article in English | MEDLINE | ID: mdl-19239259

ABSTRACT

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.


Subject(s)
Drug Discovery , Phenanthrenes/pharmacology , Receptors, Glucocorticoid/agonists , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Mass Spectrometry , Models, Molecular , Phenanthrenes/chemistry
20.
Bioorg Med Chem Lett ; 17(23): 6529-34, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17935984

ABSTRACT

Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.


Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Pyrimidines/chemistry , Pyrrolidines/chemistry , Spiro Compounds/chemistry , Animals , Enzyme Stability/drug effects , Matrix Metalloproteinase 13/metabolism , Protease Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Rats , Spiro Compounds/pharmacology , Structure-Activity Relationship
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