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Article ; Online: Comparing the Accuracy of Mini-BAL to Bronchoscopic BAL in the Diagnosis of Pneumonia Among Ventilated Patients: A Systematic Literature Review.

Tepper, John / Johnson, Sean / Parker, Connor / Collins, James / Menard, Laura / Hinkle, Laura

2023 Volume 38, Issue 12, Page(s) 1099–1107

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Humans ; Bronchoalveolar Lavage Fluid ; Respiration, Artificial ; Prospective Studies ; Pneumonia/diagnosis ; Bronchoalveolar Lavage
Language	English
Publishing date	2023-08-07
Publishing country	United States
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	632828-3
ISSN	1525-1489 ; 0885-0666
ISSN (online)	1525-1489
ISSN	0885-0666
DOI	10.1177/08850666231193379
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Article ; Online: Combined Turmeric, Vitamin C, and Vitamin D Ready-to-Drink Supplements Reduce Upper Respiratory Illness Symptoms and Gastrointestinal Discomfort in Elite Male Football Players.

Clayton, David J / Burbeary, Ross / Parker, Connor / James, Ruth M / Saward, Chris / Procter, Eleanor L / Mode, William J A / Baker, Carla / Hough, John / Williams, Neil C / Rossington, Harry / Varley, Ian

Nutrients

2024 Volume 16, Issue 2

Abstract: Elite football is associated with the increased risk of illness, although targeted supplementation can reduce illness risk. This study assessed the effects of a supplement containing turmeric root within a black pepper and fat-soluble blend, vitamin C ... ...

Abstract	Elite football is associated with the increased risk of illness, although targeted supplementation can reduce illness risk. This study assessed the effects of a supplement containing turmeric root within a black pepper and fat-soluble blend, vitamin C and vitamin D, on upper respiratory symptoms (URS), gastrointestinal symptoms (GIS), muscle soreness, and markers of inflammation and gut permeability in elite male footballers. Twenty-three footballers completed 3 weeks of no intervention (CON), followed by 16 weeks of daily consuming 60 mL of a commercially available supplement containing raw turmeric root (17.5 g, estimated to contain 700 mg of curcumin), vitamin C (1000 mg), and vitamin D3 (3000 IU/75 mcg) (SUP). URS and GIS were measured daily. Immediately (0 h), 40, and 64 h after six competitive matches (two in CON, four in SUP), the subjective soreness and plasma concentrations of creatine kinase [CK], c-reactive protein [CRP], and intestinal fatty-acid binding protein [I-FABP] were assessed. URS incidence (
MeSH term(s)	Ascorbic Acid ; Football ; Curcuma ; Vitamins ; Dietary Supplements ; Vitamin D ; C-Reactive Protein ; Creatine Kinase
Chemical Substances	Ascorbic Acid (PQ6CK8PD0R) ; Vitamins ; Vitamin D (1406-16-2) ; C-Reactive Protein (9007-41-4) ; Creatine Kinase (EC 2.7.3.2)
Language	English
Publishing date	2024-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16020243
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Article ; Online: Multisite Verification of a Targeted CFTR Polymerase Chain Reaction/Capillary Electrophoresis Assay That Evaluates Pathogenic Variants Across Diverse Ethnic and Ancestral Groups.

Hall, Bradley / Milligan, John N / Kelnar, Kevin / Hallmark, Elliot / Ashton, Jacob D / Parker, Connor A / Filipovic-Sadic, Stela / Sharp, Abigail / Eagle, Samantha / Rodgers, Nissa / Leung, Marco / Mathew, Mariam T / Grissom, Luke / Post, Rebecca / Teran, Nataša / Latham, Gary J

Archives of pathology & laboratory medicine

2024

Abstract: Context.—: Existing targeted cystic fibrosis screening assays miss important pathogenic CFTR variants in the ethnically diverse US population.: Objective.—: To evaluate the analytic performance of a multiplex polymerase chain reaction (PCR)/capillary ...

Abstract	Context.—: Existing targeted cystic fibrosis screening assays miss important pathogenic CFTR variants in the ethnically diverse US population. Objective.—: To evaluate the analytic performance of a multiplex polymerase chain reaction (PCR)/capillary electrophoresis (CE) CFTR assay panel that simultaneously interrogates primary pathogenic variants of different ethnic/ancestral groups. Design.—: Performance characteristic assessment and variant coverage comparison of the panel with a focus on ethnicity-specific CFTR variants were performed. Sample DNA was primarily from whole blood or cell lines. Detection of CFTR carriers was compared across several commercially available CFTR kits and recommended variant sets based on panel content. Results.—: The panel interrogated 65 pathogenic CFTR variants representing 92% coverage from a recent genomic sequencing survey of the US population, including 4 variants with top 5 frequency in African or Asian populations not reflected in other targeted panels. In simulation studies, the panel represented 95% of carriers across the global population, resulting in 6.9% to 19.0% higher carrier detection rate compared with 10 targeted panels or variant sets. Precision and sensitivity/specificity were 100% concordant. Multisite sample-level genotyping accuracy was 99.2%. Across PCR and CE instruments, sample-level genotyping accuracy was 97.1%, with greater than 99% agreement for all variant-level metrics. Conclusions.—: The CFTR assay achieves 92% or higher coverage of CFTR variants in diverse populations and provides improved pan-ethnic coverage of minority subgroups of the US populace. The assay can be completed within 5 hours from DNA sample to genotype, and performance data exceed acceptance criteria for analytic metrics. This assay panel content may help address gaps in ancestry-specific CFTR genotypes while providing a streamlined procedure with rapidly generated results.
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2023-0230-OA
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Article ; Online: Relationships among CFTR expression, HCO3- secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies.

Shah, Viral S / Ernst, Sarah / Tang, Xiao Xiao / Karp, Philip H / Parker, Connor P / Ostedgaard, Lynda S / Welsh, Michael J

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 113, Issue 19, Page(s) 5382–5387

Abstract: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell- ... ...

Abstract	Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10-50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl(-) secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3 (-) secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3 (-) at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR(+/-) or CFTR(+/∆F508)) expressed CFTR and secreted HCO3 (-) at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3 (-) secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl(-) secretion, the amount of CFTR is rate-limiting for HCO3 (-) secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers.
MeSH term(s)	Animals ; Animals, Newborn ; Bicarbonates/immunology ; Cystic Fibrosis/immunology ; Cystic Fibrosis/therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/immunology ; Genetic Therapy ; Immunity, Innate/immunology ; Respiratory Mucosa/immunology ; Stem Cell Transplantation ; Swine
Chemical Substances	Bicarbonates ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2016-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1604905113
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Article ; Online: Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme.

Hamilton, Matthew M / Mseeh, Faika / McAfoos, Timothy J / Leonard, Paul G / Reyna, Naphtali J / Harris, Angela L / Xu, Alan / Han, Michelle / Soth, Michael J / Czako, Barbara / Theroff, Jay P / Mandal, Pijus K / Burke, Jason P / Virgin-Downey, Brett / Petrocchi, Alessia / Pfaffinger, Dana / Rogers, Norma E / Parker, Connor A / Yu, Simon S /

Jiang, Yongying / Krapp, Stephan / Lammens, Alfred / Trevitt, Graham / Tremblay, Martin R / Mikule, Keith / Wilcoxen, Keith / Cross, Jason B / Jones, Philip / Marszalek, Joseph R / Lewis, Richard T

Journal of medicinal chemistry

2021 Volume 64, Issue 15, Page(s) 11302–11329

Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of ... ...

Abstract	Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (
MeSH term(s)	Dose-Response Relationship, Drug ; Drug Discovery ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Enzyme Inhibitors ; IDO1 protein, human ; Indoleamine-Pyrrole 2,3,-Dioxygenase
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c00679
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Discovery of 6-[(3

Czako, Barbara / Sun, Yuting / McAfoos, Timothy / Cross, Jason B / Leonard, Paul G / Burke, Jason P / Carroll, Christopher L / Feng, Ningping / Harris, Angela L / Jiang, Yongying / Kang, Zhijun / Kovacs, Jeffrey J / Mandal, Pijus / Meyers, Brooke A / Mseeh, Faika / Parker, Connor A / Yu, Simon S / Williams, Christopher C / Wu, Qi /

Di Francesco, Maria Emilia / Draetta, Giulio / Heffernan, Timothy / Marszalek, Joseph R / Kohl, Nancy E / Jones, Philip

Journal of medicinal chemistry

2021 Volume 64, Issue 20, Page(s) 15141–15169

Abstract: Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the ... ...

Abstract	Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Molecular Structure ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2021-10-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c01132
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Article ; Online: Gel-forming mucins form distinct morphologic structures in airways.

Ostedgaard, Lynda S / Moninger, Thomas O / McMenimen, James D / Sawin, Nicholas M / Parker, Connor P / Thornell, Ian M / Powers, Linda S / Gansemer, Nicholas D / Bouzek, Drake C / Cook, Daniel P / Meyerholz, David K / Abou Alaiwa, Mahmoud H / Stoltz, David A / Welsh, Michael J

Proceedings of the National Academy of Sciences of the United States of America

2017 Volume 114, Issue 26, Page(s) 6842–6847

Abstract: Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related ... ...

Abstract	Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related gel-forming mucins, MUC5B and MUC5AC. However, their morphologic structures and associations in airways that contain abundant submucosal glands and goblet cells are uncertain. Moreover, there is limited knowledge about mucins in airways not affected by inflammation, infection, or remodeling or in CF airways. Therefore, we examined airways freshly excised from newborn non-CF pigs and CF pigs before secondary manifestations develop. We found that porcine submucosal glands produce MUC5B, whereas goblet cells produce predominantly MUC5AC plus some MUC5B. We found that MUC5B emerged from submucosal gland ducts in the form of strands composed of multiple MUC5B filaments. In contrast, MUC5AC emerged from goblet cells as wispy threads and sometimes formed mucin sheets. In addition, MUC5AC often partially coated the MUC5B strands. Compared with non-CF, MUC5B more often filled CF submucosal gland ducts. MUC5AC sheets also accumulated in CF airways overlying MUC5B strands. These results reveal distinct morphology and interactions for MUC5B and MUC5AC and suggest that the two mucins make distinct contributions to mucociliary transport. Thus, they provide a framework for understanding abnormalities in disease.
MeSH term(s)	Airway Remodeling ; Animals ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Cystic Fibrosis/pathology ; Goblet Cells/metabolism ; Goblet Cells/pathology ; Mice ; Mice, Knockout ; Mucin 5AC/genetics ; Mucin 5AC/metabolism ; Mucin-5B/genetics ; Mucin-5B/metabolism
Chemical Substances	Muc5ac protein, mouse ; Muc5b protein, mouse ; Mucin 5AC ; Mucin-5B
Language	English
Publishing date	2017-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1703228114
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Article ; Online: Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R.

Czako, Barbara / Marszalek, Joseph R / Burke, Jason P / Mandal, Pijus / Leonard, Paul G / Cross, Jason B / Mseeh, Faika / Jiang, Yongying / Chang, Edward Q / Suzuki, Erika / Kovacs, Jeffrey J / Feng, Ningping / Gera, Sonal / Harris, Angela L / Liu, Zhen / Mullinax, Robert A / Pang, Jihai / Parker, Connor A / Spencer, Nakia D /

Yu, Simon S / Wu, Qi / Tremblay, Martin R / Mikule, Keith / Wilcoxen, Keith / Heffernan, Timothy P / Draetta, Giulio F / Jones, Philip

Journal of medicinal chemistry

2020 Volume 63, Issue 17, Page(s) 9888–9911

Abstract: Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially ... ...

Abstract	Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (
MeSH term(s)	Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Benzothiazoles/chemical synthesis ; Benzothiazoles/pharmacokinetics ; Benzothiazoles/therapeutic use ; Drug Stability ; Humans ; Microsomes, Liver/metabolism ; Molecular Structure ; Neoplasms/drug therapy ; Pyrimidines/chemical synthesis ; Pyrimidines/pharmacokinetics ; Pyrimidines/therapeutic use ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors ; Structure-Activity Relationship ; THP-1 Cells ; Tumor-Associated Macrophages/drug effects
Chemical Substances	Antineoplastic Agents ; Benzothiazoles ; CSF1R protein, human ; Pyrimidines ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Language	English
Publishing date	2020-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c00936
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Article ; Online: Identification of potent and selective MTH1 inhibitors.

Petrocchi, Alessia / Leo, Elisabetta / Reyna, Naphtali J / Hamilton, Matthew M / Shi, Xi / Parker, Connor A / Mseeh, Faika / Bardenhagen, Jennifer P / Leonard, Paul / Cross, Jason B / Huang, Sha / Jiang, Yongying / Cardozo, Mario / Draetta, Giulio / Marszalek, Joseph R / Toniatti, Carlo / Jones, Philip / Lewis, Richard T

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 6, Page(s) 1503–1507

Abstract: Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic ... ...

Abstract	Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology.
MeSH term(s)	DNA Repair Enzymes/antagonists & inhibitors ; DNA Repair Enzymes/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Structure ; Phosphoric Monoester Hydrolases/antagonists & inhibitors ; Phosphoric Monoester Hydrolases/metabolism ; Structure-Activity Relationship ; Substrate Specificity
Chemical Substances	Enzyme Inhibitors ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; 8-oxodGTPase (EC 3.6.1.55) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2016-02-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.02.026
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Article ; Online: Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.

Sun, Yuting / Meyers, Brooke A / Czako, Barbara / Leonard, Paul / Mseeh, Faika / Harris, Angela L / Wu, Qi / Johnson, Sarah / Parker, Connor A / Cross, Jason B / Di Francesco, Maria Emilia / Bivona, Benjamin J / Bristow, Christopher A / Burke, Jason P / Carrillo, Caroline C / Carroll, Christopher L / Chang, Qing / Feng, Ningping / Gao, Guang /

Gera, Sonal / Giuliani, Virginia / Huang, Justin K / Jiang, Yongying / Kang, Zhijun / Kovacs, Jeffrey J / Liu, Chiu-Yi / Lopez, Anastasia M / Ma, Xiaoyan / Mandal, Pijus K / McAfoos, Timothy / Miller, Meredith A / Mullinax, Robert A / Peoples, Michael / Ramamoorthy, Vandhana / Seth, Sahil / Spencer, Nakia D / Suzuki, Erika / Williams, Christopher C / Yu, Simon S / Zuniga, Andy M / Draetta, Giulio F / Marszalek, Joseph R / Heffernan, Timothy P / Kohl, Nancy E / Jones, Philip

Cancer research

2020 Volume 80, Issue 21, Page(s) 4840–4853

Abstract: Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth ... ...

Abstract	Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation
MeSH term(s)	Acrylamides/pharmacology ; Aniline Compounds/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects ; ErbB Receptors/genetics ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Mice ; Mutation ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors ; Xenograft Model Antitumor Assays
Chemical Substances	Acrylamides ; Aniline Compounds ; Antineoplastic Agents ; osimertinib (3C06JJ0Z2O) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2020-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-20-1634
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