ABSTRACT
Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).
Subject(s)
Antineoplastic Agents , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Humans , Animals , Mice , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Female , Blood-Brain Barrier/metabolism , Brain/metabolism , Melanoma/drug therapy , Melanoma/pathology , Structure-Activity Relationship , Rats , Mice, Nude , Xenograft Model Antitumor Assays , MaleABSTRACT
SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.
ABSTRACT
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Subject(s)
Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Drug Discovery , Humans , Mice , Models, Molecular , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Mice , Models, Molecular , Mutation , Proto-Oncogene Proteins p21(ras)/chemistry , Proto-Oncogene Proteins p21(ras)/genetics , Xenograft Model Antitumor AssaysABSTRACT
Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.See related commentary by Klempner and Hata, p. 20.This article is highlighted in the In This Issue feature, p. 1.
Subject(s)
Acetonitriles/therapeutic use , Adenocarcinoma of Lung/drug therapy , Antineoplastic Agents/therapeutic use , Disease Models, Animal , Lung Neoplasms/drug therapy , Mutation , Piperazines/therapeutic use , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Pyrrolidines/therapeutic use , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Animals , Apoptosis , Cell Proliferation , Clinical Trials, Phase I as Topic , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Middle Aged , Prognosis , Pyrimidines , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.
ABSTRACT
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrrolidinones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Thiazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Haplorhini , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Viral Nonstructural Proteins/metabolismABSTRACT
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hepacivirus/drug effects , Thiazines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Computational Biology , Computer Simulation , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Protein Binding , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Subject(s)
Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Quinolines/chemistry , Quinolones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Computer Simulation , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolones/chemical synthesis , Quinolones/pharmacology , Rats , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.
Subject(s)
Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Isoquinolines/chemistry , Models, Molecular , Structure-Activity RelationshipABSTRACT
We report the time courses of five solid-phase reactions obtained using single bead FTIR microspectroscopy. This time-resolved information aided in the determination of the required reaction time, the nature of the solid-phase reaction, and resin property, effectively assisting in the initial phase of our combinatorial chemistry efforts. Our results showed that solid-phase organic reactions proceed faster than generally speculated. In addition, we have shown that reactions on the surface and in the interior of the bead occur at the same rate for reactions studied. The reaction on the TentaGel resin was shown to be not faster than reactions on Wang resin, suggesting that the diffusion of the substrate into polystyrene bead copolymerized with 1% divinylbenzene is not rate-limiting. Finally, the capability of obtaining IR spectra from the partial surface of a single bead demonstrated the femtomolar detection limit of single bead FTIR microspectroscopy.