ABSTRACT
As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).
Subject(s)
Cyclohexylamines/pharmacology , Drug Discovery , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Cyclohexylamines/therapeutic use , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Structure-Activity Relationship , Substrate SpecificityABSTRACT
TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Antineoplastic Agents , Breast Neoplasms , Cell Line, Tumor , Female , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Subject(s)
Cyclohexanols/therapeutic use , Graft vs Host Disease/drug therapy , Immunologic Factors/therapeutic use , Protein Kinase C-theta/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Caco-2 Cells , Cell Proliferation/drug effects , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase C-delta/antagonists & inhibitors , Protein Kinase C-delta/metabolism , Protein Kinase C-theta/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effectsABSTRACT
INTRODUCTION: Artificial intelligence (AI) has seen a massive resurgence in recent years with wide successes in computer vision, natural language processing, and games. The similar creation of robust and accurate AI models for ADME/Tox endpoint and activity prediction would be revolutionary to drug discovery pipelines. There have been numerous demonstrations of successful applications, but a key challenge remains: how generalizable are these predictive models? AREAS COVERED: The authors present a summary of current promising components of AI models in the context of early drug discovery where ADME/Tox endpoint and activity prediction is the main driver of the iterative drug design process. Following that is a review of applicability domains and dataset construction considerations which determine generalizability bottlenecks for AI deployment. Further reviewed is the role of promising learning frameworks - multitask, transfer, and meta learning - which leverage auxiliary data to overcome issues of generalizability. EXPERT OPINION: The authors conclude that the most promising direction toward integrating reliable and informative AI models into the drug discovery pipeline is a conjunction of learned feature representations, deep learning, and novel learning frameworks. Such a solution would address the sparse and incomplete datasets that are available for key endpoints related to drug discovery.
Subject(s)
Artificial Intelligence , Drug Design , Drug Discovery , HumansABSTRACT
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
Subject(s)
Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Docetaxel/therapeutic use , Drug Design , Female , Mice, SCID , Microtubule-Associated Proteins/metabolism , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Triple Negative Breast Neoplasms/drug therapy , Animals , Cell Line, Tumor , Female , Heterografts , Humans , Mice , Mitosis/drug effects , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , RNA Splicing/drug effects , Structure-Activity Relationship , Triple Negative Breast Neoplasms/enzymologyABSTRACT
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Humans , Male , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazoles/chemistry , Triazoles/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/metabolism , Pyrazines/pharmacokinetics , Rats , Signal Transduction/drug effects , Structure-Activity Relationship , TOR Serine-Threonine Kinases/chemistry , TOR Serine-Threonine Kinases/metabolism , Triazoles/metabolism , Triazoles/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Subject(s)
2-Aminopurine/chemistry , 2-Aminopurine/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Purines/chemistry , Reperfusion Injury/enzymology , Animals , Catalytic Domain , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/pharmacology , Rats , Reperfusion Injury/drug therapy , Structure-Activity RelationshipABSTRACT
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
Subject(s)
Cyclohexanols/chemistry , Cyclohexanols/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Administration, Oral , Animals , Catalytic Domain , Cyclohexanols/administration & dosage , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Haplorhini , Idiopathic Pulmonary Fibrosis/drug therapy , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/administration & dosage , Rats , Structure-Activity RelationshipABSTRACT
A Claisen rearrangement/iodolactamization sequence starting from commercially available trifluoroacetaldehyde methyl hemiacetal, followed by a classical chemical resolution, provided enantiomerically pure 4,4-difluoro-3,3-dimethylproline (S)-1. No hazardous fluorination reagents were used, and the overall yield over 12 steps was greater than 28%.