Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists

Kindon, Nicholas D.; Andrews, Glen K.; Baxter, Andrew; Cheshire, David R.; Hemsley, Paul; Johnson, Timothy A.; Liu, Yuzhen; McGinnity, Dermot F.; McHale, Mark; Reuberson, James; Roberts, Bryan; Steele, John W.; Teobald, Barry J.; Unitt, John; Vaughan, Deborah W.; Walters, Iain A. S.; Stocks, Michael J.

doi:10.1021/acsmedchemlett.7b00315

Cited by 19 publications

(23 citation statements)

References 22 publications

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“…A clinical trial of mogamulizumab in lung and esophageal cancer patients demonstrated that the antibody was well tolerated and led to efficient depletion of Tregs [ 98 ]. Allosteric antagonists that bind to the intracellular domain of CCR4 (class II antagonists) have been developed by pharmaceutical companies, including GlaxoSmithKline (GSK2239633) and AstraZeneca (AZD-1678, AZD-2098) [ 99 , 100 ]. RAPT pharmaceuticals have developed small-molecule inhibitors of CCR4, including FLX475 and RPT193.…”

Section: Chemokines Recruit Immunosuppressive Cells Into the Tmementioning

confidence: 99%

Key chemokines direct migration of immune cells in solid tumors

2021

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Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.

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Section: Chemokines Recruit Immunosuppressive Cells Into the Tmementioning

confidence: 99%

Key chemokines direct migration of immune cells in solid tumors

2021

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“…The synthesized final compound and intermediates were screened for their CCR4 receptor inhibition activity. Compounds 366 (pIC 50 7.8) and 369 (pIC 50 8.6) were showed good potency against Human CCR4 receptor [126].…”

Section: Chlorine Containing Drugs As Miscellaneous Applicationsmentioning

confidence: 99%

Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: A critical review

Fang

Lekkala

Rakesh

et al. 2019

European Journal of Medicinal Chemistry

182

100

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a b s t r a c tAt present more than 250 FDA approved chlorine containing drugs were available in the market and many pharmaceutically important drug candidates in pre-clinical trials. Thus, it is quite obvious to expect that in coming decades there will be an even greater number of new chlorine-containing pharmaceuticals in market. Chlorinated compounds represent the family of compounds promising for use in medicinal chemistry. This review describes the recent advances in the synthesis of chlorine containing heterocyclic compounds as diverse biological agents and drugs in the pharmaceutical industries for the inspiration of the discovery and development of more potent and effective chlorinated drugs against numerous death-causing diseases.

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“…To further investigate the role of CCR3 in this mechanism, the CCR3 inhibitor SB 297006 ( White et al., 2000 ) was added to normal FLS with and without CCR3 shRNA. The CCR4 inhibitor AZD 2098 ( Kindon et al., 2017 ) was employed to examine any potential signaling/cross talk through CCR4 ( Figure S2 ). The addition of AZD 2098 or SB 297006 had no effect on S100A12 expression in normal FLS in the absence of CCL22 regardless of CCR3 knockdown.…”

Section: Resultsmentioning

confidence: 99%