ABSTRACT
Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-ß, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.
Subject(s)
Receptor Protein-Tyrosine Kinases , Urea , Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, Platelet-Derived Growth Factor beta , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacologyABSTRACT
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Animals , CHO Cells , Cell Line , Cell Line, Tumor , Cricetulus , Drug Resistance, Neoplasm/genetics , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , HCT116 Cells , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Mutation/drug effects , Mutation/geneticsABSTRACT
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
Subject(s)
Aminopyridines/pharmacology , Anilides/pharmacology , Drug Resistance, Neoplasm , Neovascularization, Pathologic , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Receptor, TIE-2/antagonists & inhibitors , Tumor Microenvironment , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Aminopyridines/chemistry , Anilides/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bevacizumab/chemistry , Bevacizumab/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Drug Design , Drug Therapy, Combination , Female , Hepatocyte Growth Factor/metabolism , Humans , Inhibitory Concentration 50 , Melanoma, Experimental , Mice , Models, Molecular , Molecular Conformation , Monocytes/drug effects , Monocytes/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-met/chemistry , Proto-Oncogene Proteins c-met/metabolism , Receptor, TIE-2/metabolism , Recombinant Proteins , Stromal Cells/drug effects , Stromal Cells/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
Subject(s)
Fusion Proteins, bcr-abl/antagonists & inhibitors , Mutation , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Design , Fusion Proteins, bcr-abl/chemistry , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Male , Mice , Mice, Inbred BALB C , Protein Conformation , Protein-Tyrosine Kinases/chemistryABSTRACT
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
Subject(s)
Adenosine Triphosphate/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phenylurea Compounds/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , HeLa Cells , Humans , Kinetics , Mitogen-Activated Protein Kinase 14/metabolism , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Phosphorylation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Picolinic Acids/chemistry , Protease Inhibitors/chemistry , Tetrazoles/chemistry , Administration, Oral , Animals , Binding Sites , Cartilage/drug effects , Cartilage/metabolism , Catalytic Domain , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Matrix Metalloproteinase 13/metabolism , Picolinic Acids/chemical synthesis , Picolinic Acids/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Zinc/chemistryABSTRACT
Compounds of the general structure A and B were investigated for their activity as lipoprotein(a), [Lp(a)], assembly (coupling) inhibitors. SAR around the amino acid derivatives (structure A) gave compound 14-6 as a potent coupling inhibitor. Oral dosing of compound 14-6 to Lp(a) transgenic mice and cymologous monkeys resulted in a>30% decrease in plasma Lp(a) levels after 1-2 weeks of treatment at 100 mg/kg/day.