ABSTRACT
SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Sulfonic Acids/therapeutic use , Sumoylation/drug effects , Ubiquitin-Activating Enzymes/antagonists & inhibitors , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Mice , Molecular Structure , Protein Binding , Protein Processing, Post-Translational/drug effects , Structure-Activity Relationship , Sulfonic Acids/chemical synthesis , Sulfonic Acids/metabolism , Ubiquitin-Activating Enzymes/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.
Subject(s)
Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tetrahydronaphthalenes/chemistry , Animals , Cell Line, Tumor , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Male , Mice , Mutagenesis , Neoplasms/drug therapy , Neoplasms/pathology , Protein Binding , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/therapeutic use , Transplantation, HeterologousABSTRACT
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
