John I. Trujillo

Abstract 5869: Preclinical characterization of CGT4255, an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration

Paul D. Larsen, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana et autres

Abstract HER2 alterations including amplification, overexpression, insertions, and point mutations are established oncogenic drivers across various solid tumor types. HER2 is amplified or overexpressed in 15-20% of breast cancer patients. In contrast, activating mutations are found in approximately 4% of cases with …

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Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis

Jennifer Lynn Duffen, Kimberly K. Crouse, Lin Ji, Amy L. Brault et autres

Interleukin-2-inducible T cell kinase is expressed by T cells and amplifies T cell receptor-dependent signals. Interleukin-2-inducible T cell kinase deletion or inhibition reduces production of interleukin-4 and interleukin-13, key drivers of atopic dermatitis. Nerve growth factor signals via the receptor tropomyosin-related kinase …

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Preclinical characterization of a novel, wild-type-sparing, JAK2 V617F mutant-selective inhibitor

Mark Joseph Chicarelli, Michelle Crow, Tanna Bettendorf, Abiezer Blandon et autres

Abstract Background The JAK2 V617F mutation is the most prevalent molecular abnormality in BCR-ABL-negative myeloproliferative neoplasms, occurring in approximately 95% of patients with polycythemia vera, and 50% of patients with essential thrombocythemia or primary myelofibrosis. This acquired point mutation in the JAK2 …

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Discovery of PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity

Mark E. Schnute, Huixian Wu, John I. Trujillo, Wei Li et autres

Abstract The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the treatment of chronic autoimmune disease as antagonism of the receptor …

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Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule

Mark E. Schnute, Gary M. Chinigo, Kentaro Futatsugi, Masaya Yamaguchi et autres

Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1–4), and inhibition of one or several …

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Abstract P4-12-16: Identification of CGT4255 an EGFR sparing, ErbB2 clinical development candidate with activity across activating mutations in systemic and CNS tumors

Mark Joseph Chicarelli, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana et autres

Abstract Alterations in ErbB2, including amplification, overexpression, insertions, and point mutations, are established oncogenic drivers in many solid tumors. These mutations are found in approximately 3–4% of breast cancers and 3% of advanced lung cancers and have emerged as mechanisms of acquired …

Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site

Leslie A. Dakin, Xing Li, J. Perry Hall, Weidong Ding et autres

Peptidylarginine deiminases (PAD1-4) are calcium dependent enzymes responsible for protein citrullination, a post-translational modification converting arginine residues to citrulline. Elevated levels of citrullinated proteins have been associated with rheumatoid arthritis, neurodegenerative diseases, and cancers. Though highly selective PAD4 inhibitors have been described, …

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Abstract 5623: Identification of CGT4255 an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration

Mark Joseph Chicarelli, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana et autres

Abstract HER2 alterations such as amplification, overexpression, insertions, and point mutations, are established oncogenic drivers in many solid tumors. Activating HER2 mutations are found in 2-4% of advanced lung cancers and have emerged as mechanisms of acquired resistance to targeted therapies. Patients …

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Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists

Brian S. Gerstenberger, Ray J. Unwalla, Kathleen A. Farley, Philippe Nuhant et autres

CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6 + …

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Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

Laura J. Byrnes, Won Young Choi, Paul Balbo, Mary Ellen Banker et autres

Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over …

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Structural basis for CCR6 modulation by allosteric antagonists

David Jonathan Wasilko, Brian S. Gerstenberger, Kathleen A. Farley, Wěi Li et autres

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures …

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Structural basis for CCR6 modulation by allosteric antagonists

David Jonathan Wasilko, Brian S. Gerstenberger, Kathleen A. Farley, Wěi Li et autres

Abstract The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases such as psoriasis and inflammatory bowel disease. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 …

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