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1.
Bioorg Med Chem ; 92: 117423, 2023 09 07.
Article in English | MEDLINE | ID: mdl-37531921

ABSTRACT

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.


Subject(s)
Interleukin-2 , Receptors, Antigen, T-Cell , Mice , Animals , Chlorocebus aethiops , Protein Serine-Threonine Kinases , COS Cells
2.
J Med Chem ; 66(13): 8666-8686, 2023 07 13.
Article in English | MEDLINE | ID: mdl-37403966

ABSTRACT

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Thiophenes , Humans , Basic Helix-Loop-Helix Transcription Factors/metabolism , Thiophenes/pharmacology , Transcription Factors , Hypoxia , Hypoxia-Inducible Factor 1, alpha Subunit
3.
ACS Med Chem Lett ; 14(5): 566-576, 2023 May 11.
Article in English | MEDLINE | ID: mdl-37197456

ABSTRACT

Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.

4.
Arthritis Rheumatol ; 75(3): 375-386, 2023 03.
Article in English | MEDLINE | ID: mdl-36054172

ABSTRACT

OBJECTIVE: To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease-modifying osteoarthritis (OA) drug. METHODS: Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intraarticular (IA) R399E doses were administered biweekly 6 times, and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in-life, and OA was assessed after 13 weeks. RESULTS: Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in 3-dimensional chondrocyte cultures. R399E also inhibited the release of interleukin-1ß (IL-1ß), IL-6, and prostaglandin E2 from cartilage with synovium, meniscal cell, and synoviocyte cultures. In rabbits, the mean difference (95% confidence interval [95% CI]) in weight bearing for R399E compared to vehicle was -5.8 (95% confidence interval [95% CI] -9.54, -2.15), -7.2 (95% CI -10.93, -3.54), and -7.7 (95% CI -11.49, -3.84) for the 0.6, 6, and 60 µg doses, respectively, 6 hours after the first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6-µg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA. CONCLUSION: R399E influences several pathologic processes contributing to OA, highlighting its potential as a disease-modifying therapy.


Subject(s)
Cartilage, Articular , Osteoarthritis , Rabbits , Animals , Sheep , Factor V/metabolism , Factor V/therapeutic use , Cartilage, Articular/pathology , Osteoarthritis/metabolism , Anterior Cruciate Ligament/surgery , Anterior Cruciate Ligament/metabolism , Anterior Cruciate Ligament/pathology , Cell Differentiation
5.
J Med Chem ; 65(13): 9206-9229, 2022 07 14.
Article in English | MEDLINE | ID: mdl-35763499

ABSTRACT

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.


Subject(s)
Neoplasms , Transcription Factors , Animals , Mice , TEA Domain Transcription Factors , Transcription Factors/metabolism
6.
J Med Chem ; 64(14): 10230-10245, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34228444

ABSTRACT

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (ß1, ß2, and ß5). LMP7 (ß5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.


Subject(s)
Drug Discovery , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/chemistry , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Structure-Activity Relationship
7.
J Med Chem ; 64(14): 10371-10392, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34255518

ABSTRACT

Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth. Herein, the identification of a screening hit series and its optimization through scaffold hopping and SAR exploration is described. The systematic assessment delivered M2912, a compound with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compound in colorectal xenograft models in vivo.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Tankyrases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Humans , Mice , Mice, SCID , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Structure-Activity Relationship , Tankyrases/metabolism
8.
Mol Cancer Ther ; 20(8): 1378-1387, 2021 08.
Article in English | MEDLINE | ID: mdl-34045234

ABSTRACT

Large multifunctional peptidase 7 (LMP7/ß5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells both in vitro and in vivo Furthermore, M3258 showed superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in patients with multiple myeloma (NCT04075721).


Subject(s)
Boronic Acids/pharmacology , Drug Resistance, Neoplasm/drug effects , Furans/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Multiple Myeloma/drug therapy , Proteasome Endopeptidase Complex/chemistry , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis , Boron Compounds/administration & dosage , Bortezomib/administration & dosage , Cell Proliferation , Female , Glycine/administration & dosage , Glycine/analogs & derivatives , Humans , Mice , Mice, Nude , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Proteolysis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
9.
Cell Chem Biol ; 28(5): 686-698.e7, 2021 05 20.
Article in English | MEDLINE | ID: mdl-33497606

ABSTRACT

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.


Subject(s)
Focal Adhesion Kinase 1/antagonists & inhibitors , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Sulfonamides/pharmacology , Cells, Cultured , Female , Focal Adhesion Kinase 1/metabolism , HEK293 Cells , Humans , Indoles/chemical synthesis , Indoles/chemistry , Kinetics , Ligands , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
10.
J Pharmacol Exp Ther ; 376(3): 397-409, 2021 03.
Article in English | MEDLINE | ID: mdl-33328334

ABSTRACT

Toll-like receptor (TLR) 7 and TLR8 are transmembrane receptors that recognize single-stranded RNA. Activation of these receptors results in immune cell stimulation and inflammatory cytokine production, which is normally a protective host response. However, aberrant activation of TLR7/8 is potentially pathogenic and linked to progression of certain autoimmune diseases such as lupus. Thus, we hypothesize that an inhibitor that blocks TLR7/8 would be an effective therapeutic treatment. Prior efforts to develop inhibitors of TLR7/8 have been largely unsuccessful as a result of the challenge of producing a small-molecule inhibitor for these difficult targets. Here, we report the characterization of M5049 and compound 2, molecules which were discovered in a medicinal chemistry campaign to produce dual TLR7/8 inhibitors with drug-like properties. Both compounds showed potent and selective activity in a range of cellular assays for inhibition of TLR7/8 and block synthetic ligands and natural endogenous RNA ligands such as microRNA and Alu RNA. M5049 was found to be potent in vivo as TLR7/8 inhibition efficaciously treated disease in several murine lupus models and, interestingly, was efficacious in a disease context in which TLR7/8 activity has not previously been considered a primary disease driver. Furthermore, M5049 had greater potency in disease models than expected based on its in vitro potency and pharmacokinetic/pharmacodynamic properties. Because of its preferential accumulation in tissues, and ability to block multiple TLR7/8 RNA ligands, M5049 may be efficacious in treating autoimmunity and has the potential to provide benefit to a variety of patients with varying disease pathogenesis. SIGNIFICANCE STATEMENT: This study reports discovery of a novel toll-like receptor (TLR) 7 and TLR8 inhibitor (M5049); characterizes its binding mode, potency/selectivity, and pharmacokinetic and pharmacodynamic properties; and demonstrates its potential for treating autoimmune diseases in two mouse lupus models. TLR7/8 inhibition is unique in that it may block both innate and adaptive autoimmunity; thus, this study suggests that M5049 has the potential to benefit patients with autoimmune diseases.


Subject(s)
Autoimmunity/drug effects , Drug Discovery , Toll-Like Receptor 7/antagonists & inhibitors , Toll-Like Receptor 8/antagonists & inhibitors , Animals , Female , Gene Expression Regulation/drug effects , HEK293 Cells , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Protein Conformation , Toll-Like Receptor 7/chemistry , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/chemistry , Toll-Like Receptor 8/metabolism
11.
J Chem Inf Model ; 60(11): 5457-5474, 2020 11 23.
Article in English | MEDLINE | ID: mdl-32813975

ABSTRACT

Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.


Subject(s)
Drug Discovery , Ligands , Prospective Studies , Retrospective Studies , Thermodynamics
12.
Oncoimmunology ; 9(1): 1744921, 2020.
Article in English | MEDLINE | ID: mdl-32313722

ABSTRACT

T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional and exhausted T cells, and engagement of TIM-3 with its ligands promotes TIM-3-mediated T cell inhibition. Antagonistic ligand-blocking anti-TIM-3 antibodies have the potential to abrogate T cell inhibition, activate antigen-specific T cells, and enhance anti-tumor immunity. Here we describe M6903, a fully human anti-TIM-3 antibody without effector function and with high affinity and selectivity to TIM-3. We demonstrate that M6903 blocks the binding of TIM-3 to three of its ligands, phosphatidylserine (PtdSer), carcinoembryonic antigen cell adhesion-related molecule 1 (CEACAM1), and galectin 9 (Gal-9). These results are supported by an atomic resolution crystal structure and functional assays, which demonstrate that M6903 monotherapy enhanced T cell activation. This activation was further enhanced by the combination of M6903 with bintrafusp alfa, a bifunctional fusion protein that simultaneously blocks the transforming growth factor-ß (TGF-ß) and programmed death ligand 1 (PD-L1) pathways. M6903 and bintrafusp alfa combination therapy also enhanced anti-tumor efficacy in huTIM-3 knock-in mice, relative to either monotherapy. These in vitro and in vivo data, along with favorable pharmacokinetics in marmoset monkeys, suggest that M6903 as a monotherapy warrants further pre-clinical assessment and that M6903 and bintrafusp alfa may be a promising combination therapy in the clinic.


Subject(s)
Hepatitis A Virus Cellular Receptor 2 , Neoplasms , Animals , Antibodies, Monoclonal , Lymphocyte Activation , Mice , T-Lymphocytes
13.
J Med Chem ; 62(24): 11119-11134, 2019 12 26.
Article in English | MEDLINE | ID: mdl-31725285

ABSTRACT

The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound 1a suffered from enterohepatic circulation, preventing further development. Nevertheless, 1a served as a starting point for further optimization. Maintaining potent antiproliferation activity, while improving other compound properties, enabled the generation of an attractive array of new MetAP-2 inhibitors. The most promising derivatives were identified by a multiparameter analysis of the compound properties. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability, and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede the growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to the nomination of the clinical development compound M8891, which is currently in phase I clinical testing in oncology patients.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Glioma/drug therapy , Indoles/pharmacology , Methionyl Aminopeptidases/antagonists & inhibitors , A549 Cells , Animals , Antineoplastic Agents/chemistry , Apoptosis , Caco-2 Cells , Cell Proliferation , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Enzyme Inhibitors/chemistry , Female , Glioma/metabolism , Glioma/pathology , Humans , Indoles/chemistry , Mice , Mice, Nude , Models, Molecular , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
14.
J Chem Inf Model ; 59(12): 5135-5147, 2019 12 23.
Article in English | MEDLINE | ID: mdl-31697501

ABSTRACT

We here report on nonequilibrium targeted molecular dynamics simulations as a tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean nonequilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries. We propose ligand conformational changes and protein-ligand nonbonded interactions to impact on unbinding rates. Ligands may remain longer at the protein if they exhibit strong electrostatic and/or van der Waals interactions with the target. In the case of ligands with a rigid chemical scaffold that exhibit longer residence times, transient electrostatic interactions with the protein appear to facilitate unbinding. Our results imply that understanding the unbinding pathway and the protein-ligand interactions along this path is crucial for the prediction of small molecule ligands with defined unbinding kinetics.


Subject(s)
Molecular Dynamics Simulation , Proteins/metabolism , Kinetics , Ligands , Protein Binding , Protein Conformation , Proteins/chemistry , Static Electricity
15.
J Med Chem ; 62(17): 7897-7909, 2019 09 12.
Article in English | MEDLINE | ID: mdl-31381853

ABSTRACT

Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound 5k, a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model in vivo.


Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Quinazolines/pharmacology , Tankyrases/antagonists & inhibitors , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship , Tankyrases/chemistry , Tankyrases/metabolism
16.
J Med Chem ; 62(10): 5025-5039, 2019 05 23.
Article in English | MEDLINE | ID: mdl-30939017

ABSTRACT

Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 µM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Methionyl Aminopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Male , Metals/chemistry , Methionine/chemistry , Mice, Nude , Molecular Conformation , Structure-Activity Relationship
17.
J Chem Inf Model ; 59(1): 535-549, 2019 01 28.
Article in English | MEDLINE | ID: mdl-30500211

ABSTRACT

Computational approaches currently assist medicinal chemistry through the entire drug discovery pipeline. However, while several computational tools and strategies are available to predict binding affinity, predicting the drug-target binding kinetics is still a matter of ongoing research. Here, we challenge scaled molecular dynamics simulations to assess the off-rates for a series of structurally diverse inhibitors of the heat shock protein 90 (Hsp90) covering 3 orders of magnitude in their experimental residence times. The derived computational predictions are in overall good agreement with experimental data. Aside from the estimation of exit times, unbinding pathways were assessed through dimensionality reduction techniques. The data analysis framework proposed in this work could lead to better understanding of the mechanistic aspects related to the observed kinetic behavior.


Subject(s)
HSP90 Heat-Shock Proteins/metabolism , Molecular Dynamics Simulation , Pharmaceutical Preparations/metabolism , HSP90 Heat-Shock Proteins/chemistry , Humans , Kinetics , Ligands , Protein Binding , Protein Conformation
18.
Angew Chem Int Ed Engl ; 57(31): 9955-9960, 2018 07 26.
Article in English | MEDLINE | ID: mdl-29772085

ABSTRACT

Investigation of protein-ligand interactions is crucial during early drug-discovery processes. ATR-FTIR spectroscopy can detect label-free protein-ligand interactions with high spatiotemporal resolution. Here we immobilized, as an example, the heat shock protein HSP90 on an ATR crystal. This protein is an important molecular target for drugs against several diseases including cancer. With our novel approach we investigated a ligand-induced secondary structural change. Two specific binding modes of 19 drug-like compounds were analyzed. Different binding modes can lead to different efficacy and specificity of different drugs. In addition, the kobs values of ligand dissociation were obtained. The results were validated by X-ray crystallography for the structural change and by SPR experiments for the dissociation kinetics, but our method yields all data in a single and simple experiment.


Subject(s)
Drug Discovery , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/pharmacology , Triazoles/pharmacology , Crystallography, X-Ray , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , Humans , Ligands , Models, Molecular , Molecular Conformation , Pyrazoles/chemistry , Spectroscopy, Fourier Transform Infrared , Time Factors , Triazoles/chemistry
19.
J Chem Theory Comput ; 14(7): 3859-3869, 2018 Jul 10.
Article in English | MEDLINE | ID: mdl-29768913

ABSTRACT

Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compounds and less than 2.0τ within congeneric series. Analysis of dissociation trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.


Subject(s)
HSP90 Heat-Shock Proteins/metabolism , Binding Sites , Drug Discovery , HSP90 Heat-Shock Proteins/chemistry , Humans , Kinetics , Ligands , Molecular Dynamics Simulation , Protein Binding , Protein Domains
20.
J Med Chem ; 61(10): 4397-4411, 2018 05 24.
Article in English | MEDLINE | ID: mdl-29701469

ABSTRACT

Residence time and more recently the association rate constant kon are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant kon decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Drug Resistance, Neoplasm , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Molecular Dynamics Simulation , Binding Sites , Crystallography, X-Ray , HSP90 Heat-Shock Proteins/metabolism , Humans , Ligands , Models, Molecular , Molecular Structure , Protein Binding , Protein Conformation
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