ABSTRACT
Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.
Subject(s)
Antineoplastic Agents , Giant Cell Tumor of Tendon Sheath , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , DCC Receptor , Giant Cell Tumor of Tendon Sheath/drug therapy , Giant Cell Tumor of Tendon Sheath/pathology , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases , Receptor, Macrophage Colony-Stimulating FactorABSTRACT
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
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.
Subject(s)
Breast Neoplasms/drug therapy , Macrophages/drug effects , Neovascularization, Pathologic/drug therapy , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Pyrazoles/pharmacology , Pyridines/pharmacology , Quinolines/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Angiopoietins/antagonists & inhibitors , Angiopoietins/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinolines/therapeutic use , Receptor, TIE-2/genetics , Signal Transduction/drug effects , Tumor Microenvironment/drug effectsABSTRACT
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
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , ras Proteins/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor/drug effects , Chemistry Techniques, Synthetic , Dogs , Female , Half-Life , Humans , Male , Mice, Nude , Molecular Targeted Therapy , Mutation , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor Assays , ras Proteins/geneticsABSTRACT
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.
