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Francis, Rhys (2024) Design, Synthesis, and Development of Novel Intracellular Allosteric Modulators of CXC Chemokine Receptor 1 and 2. PhD thesis, University of Nottingham.

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Abstract

Chemokine receptors, CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2) play pivotal roles in various neutrophil-mediated inflammatory diseases, including COPD, asthma, and psoriasis. Additionally, evidence is mounting for the involvement of neutrophils and the CXCL8-CXCR1/2 axis in the progression and metastasis in multiple cancers. Their role in multiple disease states has made them an appealing candidate for therapeutic intervention for over a decade.

Much of the existing research of CXCR1 and CXCR2 has centred on their interaction with the endogenous chemokine CXCL8 and the ensuing CXCL8-CXCR1/2 axis in disease pathogenesis. However, despite promising preclinical evidence, challenges persist in translating these findings into effective therapies, particularly with intracellular allosteric binding site antagonists such as navarixin (2) and AZD5069 (3). The recent setbacks faced by these small molecules in phase II trials underscore the need for a comprehensive evaluation of the clinical effectiveness of CXCR1 and CXCR2 antagonists in inflammatory diseases. Additionally, emerging evidence points to distinct roles played by CXCR1 and CXCR2 in disease progression, particularly in cancer. To further evaluate the therapeutic potential of antagonists targeting CXCR1 and CXCR2, the use of pharmacological tool compounds is proposed to elucidate the intricate signalling pathways leading to their effects.

The recent publication of the CXCR2 crystal structure bound to NAM 00767013 (1) provides a promising foundation for the computer-aided design of intracellular allosteric antagonists. Leveraging this structural insight offers a valuable opportunity to develop novel therapeutics targeting CXCR2 and the closely related CXCR1.

This thesis reports the design, synthesis and pharmacological characterisation of a series of novel compounds belonging to the 3,4-diamino-3-cyclobutene-1,2-dione class of NAMs as part of an structure activity relationship study to further explore the chemical space around lead compound, navarixin (2) and providing evidence for modifications towards achieving dual CXCR1/CXCR2 activity, and potentially leading to CXCR1 selectivity over CXCR2, which could be prove useful in further studies of these receptors.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Mistry, Shailesh Laughton, Charles Holliday, Nicholas
Keywords:	Chemokine GPCR CADD SBDD CXCR1 CXCR2 Homology modelling
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	79820
Depositing User:	Francis, Rhys
Date Deposited:	13 Dec 2024 04:40
Last Modified:	13 Dec 2024 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/79820

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