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Your search keyword '"Dowling, James E."' showing total 7 results
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7 results on '"Dowling, James E."'

1. The Fibronectin-Binding Integrins System as a Contributor to PAH Pathogenesis

Author

Lemay, Sarah-Eve, primary, Montesinos, Mónica S, additional, Grobs, Yann, additional, Yokokawa, Tetsuro, additional, Shimauchi, Tsukasa, additional, Breuils-Bonnet, Sandra, additional, Martineau, Sandra, additional, Bourgeois, Alice, additional, Salem, Mabrouka, additional, Théberge, Charlie, additional, El Kabbout, Reem, additional, Romanet, Charlotte, additional, Lu, Min, additional, Huang, Xinqiang, additional, Dowling, James E, additional, Ray, Adrian S, additional, Potus, François, additional, Provencher, Steeve, additional, Boucherat, Olivier, additional, and Bonnet, Sébastien, additional

Published
2023
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2. Optimization of a Series of Novel, Potent and Selective Macrocyclic SYK Inhibitors

Author

Grimster, Neil Patrick, primary, Gingipalli, Lakshmaiah, additional, Balazs, Amber, additional, Barlaam, Bernard, additional, Boiko, Scott, additional, Boyd, Scott, additional, Dry, Hannah, additional, Goldberg, Frederick W., additional, Ikeda, Tim, additional, Johnson, Tony, additional, Kawatkar, Sameer, additional, Kemmitt, Paul, additional, Lamont, Scott, additional, Lorthioir, Olivier, additional, Mfuh, Adelphe, additional, Patel, Joe, additional, Pike, Andy, additional, Read, Jon, additional, Romero, Romulo, additional, Sarkar, Ujjal, additional, Sha, Li, additional, Simpson, Iain, additional, Song, Kun, additional, Su, Qibin, additional, Wang, Haixia, additional, Watson, David, additional, Wu, Allan, additional, Zehnder, Troy E., additional, Zheng, XiaoLan, additional, Li, Shaolu, additional, Dong, Zhiqiang, additional, Yang, Dejian, additional, Song, Yanwei, additional, Wang, Peng, additional, Liu, Xuemei, additional, Dowling, James E., additional, and Edmondson, Scott D., additional

Published
2023
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3. Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors

Author

Grimster, Neil P., Gingipalli, Lakshmaiah, Balazs, Amber, Barlaam, Bernard, Boiko, Scott, Boyd, Scott, Dry, Hannah, Goldberg, Frederick W., Ikeda, Tim, Johnson, Tony, Kawatkar, Sameer, Kemmitt, Paul, Lamont, Scott, Lorthioir, Olivier, Mfuh, Adelphe, Patel, Joe, Pike, Andy, Read, Jon, Romero, Romulo, Sarkar, Ujjal, Sha, Li, Simpson, Iain, Song, Kun, Su, Qibin, Wang, Haixia, Watson, David, Wu, Allan, Zehnder, Troy E., Zheng, XiaoLan, Li, Shaolu, Dong, Zhiqiang, Yang, Dejian, Song, Yanwei, Wang, Peng, Liu, Xuemei, Dowling, James E., and Edmondson, Scott D.

Published
2023
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4. Abstract 10717: Role of Integrin Signaling in Pulmonary Arterial Hypertension

Author

Lemay, Sarah-eve, primary, Montesinos, Mónica S, additional, Grobs, Yann, additional, Shimauchi, Tsukasa, additional, Breuils Bonnet, Sandra, additional, Martineau, Sandra, additional, Huang, Xinqiang, additional, Dowling, James E, additional, Lu, Min, additional, Ray, Adrian S, additional, Paulin, Roxane, additional, Potus, François, additional, Provencher, Steeve, additional, BOUCHERAT, Olivier, additional, and Bonnet, Sebastien, additional

Published
2021
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5. The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis

Author

Harrison, Bryce A., Dowling, James E., Bursavich, Matthew G., Troast, Dawn M., Chong, Katherine M., Hahn, Kristopher N., Zhong, Cheng, Mulvihill, Kristen M., Nguyen, Hanh, Monroy, Meghan F., Qiao, Qi, Sosa, Brian, Mostafavi, Siavash, Smukste, Inese, Lee, Dooyoung, Cappellucci, Laura, Konopka, Elizabeth H., Nowakowski, Patrycja, Stawski, Lukasz, Senices, Mayra, Nguyen, Minh Hai, Kapoor, Parmita S., Luus, Lia, Sullivan, Andrew, Bortolato, Andrea, Svensson, Mats, Hickey, Eugene R., Konze, Kyle D., Day, Tyler, Kim, Byungchan, Negri, Ana, Gerasyuto, Aleksey I., Moy, Terence I., Lu, Min, Ray, Adrian S., Wang, Liangsu, Cui, Dan, Lin, Fu-Yang, Lippa, Blaise, and Rogers, Bruce N.

Abstract

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

Published
2024
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6. Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265PDiffuse Large B-Cell Lymphoma

Author

Scott, James S., Degorce, Sébastien L., Anjum, Rana, Culshaw, Janet, Davies, Robert D. M., Davies, Nichola L., Dillman, Keith S., Dowling, James E., Drew, Lisa, Ferguson, Andrew D., Groombridge, Sam D., Halsall, Christopher T., Hudson, Julian A., Lamont, Scott, Lindsay, Nicola A., Marden, Stacey K., Mayo, Michele F., Pease, J. Elizabeth, Perkins, David R., Pink, Jennifer H., Robb, Graeme R., Rosen, Alan, Shen, Minhui, McWhirter, Claire, and Wu, Dedong

Abstract

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265Pdiffuse large B-cell lymphoma (DLBCL). Compound 28was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

Published
2024
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7. Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies.

Author

Lemay SE, Montesinos MS, Grobs Y, Yokokawa T, Shimauchi T, Romanet C, Sauvaget M, Breuils-Bonnet S, Bourgeois A, Théberge C, Pelletier A, El Kabbout R, Martineau S, Yamamoto K, Ray AS, Lippa B, Goodwin B, Lin FY, Wang H, Dowling JE, Lu M, Qiao Q, McTeague TA, Moy TI, Potus F, Provencher S, Boucherat O, and Bonnet S

Abstract

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5β1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5β1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5β1 integrin inhibition as a promising therapy for pulmonary hypertension., One Sentence Summary: The α5β1 integrin plays a crucial role in pulmonary vascular remodeling.

Published
2024
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