ABSTRACT
Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound 1 showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4. In this report, chemical modification intended to improve TRK inhibition and avoid CYP3A4 induction enabled us to identify an orally bioavailable, selective, and potent TRK inhibitor 7.
Subject(s)
Neoplasms , Tropomyosin , Cell Proliferation , Cytochrome P-450 CYP3A , Humans , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Receptor, trkAABSTRACT
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D-modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Drug Discovery , Pyrazoles/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Haplorhini , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
Subject(s)
Antineoplastic Agents/chemistry , Benzamides/chemistry , MAP Kinase Kinase Kinases/antagonists & inhibitors , Oxazines/chemistry , Protein Kinase Inhibitors/chemistry , Administration, Oral , Allosteric Regulation , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzamides/administration & dosage , Benzamides/pharmacology , Humans , Models, Molecular , Oxazines/administration & dosage , Oxazines/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacologyABSTRACT
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Prodrugs/chemical synthesis , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Camptothecin/blood , Camptothecin/chemical synthesis , Camptothecin/chemistry , Camptothecin/pharmacokinetics , DNA Topoisomerases, Type I/metabolism , Dogs , Haplorhini , Humans , Hydrogen-Ion Concentration , Irinotecan , Mice , Mice, Nude , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Rats , Topoisomerase I Inhibitors , Transplantation, Heterologous , Water/chemistryABSTRACT
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Camptothecin/chemical synthesis , Camptothecin/chemistry , Camptothecin/pharmacology , Cell Line, Tumor , DNA Topoisomerases, Type I/metabolism , Humans , Mice , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.
