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1.
J Med Chem ; 66(14): 9784-9796, 2023 07 27.
Article in English | MEDLINE | ID: mdl-37406165

ABSTRACT

Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein-ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein-ligand system amenable to studies of other intermolecular interactions.


Subject(s)
Proteins , Tyrosine , Models, Molecular , Ligands , Proteins/metabolism
2.
J Med Chem ; 66(2): 1221-1238, 2023 01 26.
Article in English | MEDLINE | ID: mdl-36607408

ABSTRACT

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.


Subject(s)
Chagas Disease , Trypanocidal Agents , Trypanosoma cruzi , Humans , Chagas Disease/drug therapy , Quinazolines/pharmacology , Quinazolines/therapeutic use , Structure-Activity Relationship , Trypanocidal Agents/therapeutic use , Trypanocidal Agents/pharmacokinetics
3.
J Med Chem ; 65(16): 11388-11403, 2022 08 25.
Article in English | MEDLINE | ID: mdl-35972896

ABSTRACT

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting about 145 million people worldwide. Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. Herein, we describe the discovery of a series of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as novel macrofilaricides for the treatment of human filarial infections.


Subject(s)
Elephantiasis, Filarial , Onchocerciasis , Adult , Amines , Humans
4.
Article in English | MEDLINE | ID: mdl-35834918

ABSTRACT

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans, microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa, respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi, the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200-400 and low lipophilicity, logP <4, and pharmacokinetic properties, rat and human liver S9 stability of ≥70% remaining at 60 min, and AUC exposures above 3 µM h. This platform demonstrated the successful establishment of a screening cascade which resulted in the discovery of potential novel macrofilaricidal compounds for futher drug discovery lead optimization efforts. This screening cascade identified two distinct chemical series wherein one compound produced a significant 68% reduction of adult Litomosoides sigmodontis in the mouse model. Successful demonstration of efficacy prompted lead optimization medicinal chemistry efforts for this novel series.


Subject(s)
Brugia malayi , Onchocerciasis , Parasites , Adult , Animals , Caenorhabditis elegans , Cats , Cattle , Drug Discovery , Humans , Mice , Onchocerca , Onchocerciasis/parasitology , Rats
5.
J Med Chem ; 64(24): 18193-18208, 2021 12 23.
Article in English | MEDLINE | ID: mdl-34894681

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 Specificity
6.
RSC Med Chem ; 12(3): 384-393, 2021 Jan 21.
Article in English | MEDLINE | ID: mdl-34041487

ABSTRACT

An innovative pre-competitive virtual screening collaboration was engaged to validate and subsequently explore an imidazo[1,2-a]pyridine screening hit for visceral leishmaniasis. In silico probing of five proprietary pharmaceutical company libraries enabled rapid expansion of the hit chemotype, alleviating initial concerns about the core chemical structure while simultaneously improving antiparasitic activity and selectivity index relative to the background cell line. Subsequent hit optimization informed by the structure-activity relationship enabled by this virtual screening allowed thorough investigation of the pharmacophore, opening avenues for further improvement and optimization of the chemical series.

7.
PLoS Pathog ; 16(6): e1008567, 2020 06.
Article in English | MEDLINE | ID: mdl-32574211

ABSTRACT

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.


Subject(s)
Antitubercular Agents/pharmacology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Mycobacterium tuberculosis/metabolism , Rifampin/pharmacology , Tuberculosis , Animals , Disease Models, Animal , Female , Mice , Mycobacterium tuberculosis/pathogenicity , Tuberculosis/drug therapy , Tuberculosis/metabolism , Tuberculosis/pathology
8.
ACS Med Chem Lett ; 9(3): 210-214, 2018 Mar 08.
Article in English | MEDLINE | ID: mdl-29541362

ABSTRACT

Lymphatic filariasis infects over 120 million people worldwide and can lead to significant disfigurement and disease. Resistance is emerging with current treatments, and these therapies have dose limiting adverse events; consequently new targets are needed. One approach to achieve this goal is inhibition of parasitic protein kinases involved in circumventing host defense mechanisms. This report describes structure-activity relationships leading to the identification of a potent, orally bioavailable stress activated protein kinase inhibitor that may be used to investigate this hypothesis.

9.
J Med Chem ; 60(21): 8989-9002, 2017 11 09.
Article in English | MEDLINE | ID: mdl-28991472

ABSTRACT

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/enzymology
10.
Methods Mol Biol ; 1608: 271-297, 2017.
Article in English | MEDLINE | ID: mdl-28695516

ABSTRACT

This chapter describes the approaches taken in the development of the first PARP inhibitor to enter clinical trial, rucaparib (now called Rubraca), in 2003. We describe the general principles of crystal-based drug design, the purification and crystallization of the PARP-1 catalytic domain and how this was used to develop highly potent PARP inhibitors, based on the nicotinamide pharmacophore. Several methods have been used to determine the inhibitory potency in cell-free and whole cell assays, each described with reference to its advantages and disadvantages.


Subject(s)
Enzyme Inhibitors/chemistry , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Animals , Catalytic Domain , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
11.
J Med Chem ; 58(13): 5323-33, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26083478

ABSTRACT

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, Cultured
12.
J Med Chem ; 58(14): 5599-608, 2015 Jul 23.
Article in English | MEDLINE | ID: mdl-26102506

ABSTRACT

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 Assays
13.
Mol Cancer Ther ; 14(6): 1295-305, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25855786

ABSTRACT

mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway, which is frequently mutated in many cancers, leading to hyperactivation of mTOR signaling. Although rapamycin analogues, allosteric inhibitors that target only the mTORC1 complex, have shown some clinical activity, it is hypothesized that mTOR kinase inhibitors, blocking both mTORC1 and mTORC2 signaling, will have expanded therapeutic potential. Here, we describe the preclinical characterization of CC-223. CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. Growth inhibitory activity was demonstrated in hematologic and solid tumor cell lines. mTOR kinase inhibition in cells, by CC-223, resulted in more complete inhibition of the mTOR pathway biomarkers and improved antiproliferative activity as compared with rapamycin. Growth inhibitory activity and apoptosis was demonstrated in a panel of hematologic cancer cell lines. Correlative analysis revealed that IRF4 expression level associates with resistance, whereas mTOR pathway activation seems to associate with sensitivity. Treatment with CC-223 afforded in vivo tumor biomarker inhibition in tumor-bearing mice, after a single oral dose. CC-223 exhibited dose-dependent tumor growth inhibition in multiple solid tumor xenografts. Significant inhibition of mTOR pathway markers pS6RP and pAKT in CC-223-treated tumors suggests that the observed antitumor activity of CC-223 was mediated through inhibition of both mTORC1 and mTORC2. CC-223 is currently in phase I clinical trials.


Subject(s)
Neoplasms/drug therapy , Pyrazines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor Assays , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Female , HCT116 Cells , HEK293 Cells , Humans , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Mice, SCID , Molecular Structure , Multiprotein Complexes/antagonists & inhibitors , Multiprotein Complexes/metabolism , Neoplasms/blood supply , Neoplasms/metabolism , Neovascularization, Pathologic/prevention & control , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , TOR Serine-Threonine Kinases/metabolism , Tumor Burden/drug effects
14.
Methods Mol Biol ; 780: 463-89, 2011.
Article in English | MEDLINE | ID: mdl-21870278

ABSTRACT

This chapter describes the approaches taken in the development of the first PARP inhibitor to enter into clinical trial, AG-014699. We describe the general principles of crystal-based drug design, the purification, and crystallization of the PARP-1 catalytic domain, and how this approach was used to develop highly potent PARP inhibitors based on the nicotinamide pharmacophore. Several methods have been used to determine the inhibitory potency of designed inhibitors in cell-free and whole cell assays; each is described with reference to its advantages and disadvantages.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Crystallography , Drug Design , Enzyme Inhibitors/pharmacology , Humans
15.
Mol Cancer Ther ; 6(3): 945-56, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17363489

ABSTRACT

Poly(ADP-ribose) polymerase (PARP)-1 (EC 2.4.2.30) is a nuclear enzyme that promotes the base excision repair of DNA breaks. Inhibition of PARP-1 enhances the efficacy of DNA alkylating agents, topoisomerase I poisons, and ionizing radiation. Our aim was to identify a PARP inhibitor for clinical trial from a panel of 42 potent PARP inhibitors (K(i), 1.4-15.1 nmol/L) based on the quinazolinone, benzimidazole, tricyclic benzimidazole, tricyclic indole, and tricyclic indole-1-one core structures. We evaluated chemosensitization of temozolomide and topotecan using LoVo and SW620 human colorectal cells; in vitro radiosensitization was measured using LoVo cells, and the enhancement of antitumor activity of temozolomide was evaluated in mice bearing SW620 xenografts. Excellent chemopotentiation and radiopotentiation were observed in vitro, with 17 of the compounds causing a greater temozolomide and topotecan sensitization than the benchmark inhibitor AG14361 and 10 compounds were more potent radiosensitizers than AG14361. In tumor-bearing mice, none of the compounds were toxic when given alone, and the antitumor activity of the PARP inhibitor-temozolomide combinations was unrelated to toxicity. Compounds that were more potent chemosensitizers in vivo than AG14361 were also more potent in vitro, validating in vitro assays as a prescreen. These studies have identified a compound, AG14447, as a PARP inhibitor with outstanding in vivo chemosensitization potency at tolerable doses, which is at least 10 times more potent than the initial lead, AG14361. The phosphate salt of AG14447 (AG014699), which has improved aqueous solubility, has been selected for clinical trial.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Line, Tumor/drug effects , Cell Line, Tumor/radiation effects , Colorectal Neoplasms/radiotherapy , DNA Repair/drug effects , DNA Repair/radiation effects , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Gamma Rays , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Maximum Tolerated Dose , Mice , Mice, Nude , Poly(ADP-ribose) Polymerases/metabolism , Structure-Activity Relationship , Temozolomide , Topoisomerase I Inhibitors , Topotecan/pharmacology
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