Journal article

Lead optimisation of OXS007417: in vivo PK profile and hERG liability modulation to optimise a small molecule differentiation agent for the potential treatment of acute myeloid leukaemia †

Abstract:: The development of a safe, efficacious, and widely effective differentiation therapy for AML would dramatically improve the outlook for many patients worldwide. To this aim, our laboratory has discovered a class of differentiation agents that demonstrate tumour regression in murine models in vivo. Herein, we report a lead optimisation process around compound OXS007417, which led to improved potency, solubility, metabolic stability, and off-target toxicity of this compound class. A hERG liability was investigated and successfully alleviated through addition of nitrogen atoms into key positions of the compound. OXS008255 and OXS008474 demonstrated an improved murine PK profile in respect to OXS007417 and a delay in tumour growth in a subcutaneous in vivo model using HL-60 cells.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Cogswell, T. J., Josa-Culleré, L., Zimmer, D., Galan, S. R. G., Jay-Smith, M., Harris, K. S., Bataille, C. J. R., Jackson, T. R., Zhang, D., Davies, S. G., Vyas, P., Milne, T. A., Wynne, G. M., & Russell, A. J. (2024). Lead optimisation of OXS007417: in vivo PK profile and hERG liability modulation to optimise a small molecule differentiation agent for the potential treatment of acute myeloid leukaemia †. RSC Medicinal Chemistry, 15, 3495–3506.

MLA Style

Cogswell, T. J., et al. “Lead Optimisation of OXS007417: in Vivo PK Profile and HERG Liability Modulation to Optimise a Small Molecule Differentiation Agent for the Potential Treatment of Acute Myeloid Leukaemia †.” RSC Medicinal Chemistry, vol. 15, Royal Society of Chemistry, 2024, pp. 3495–506.

Chicago Style

Cogswell, TJ, L Josa-Culleré, D Zimmer, SRG Galan, M Jay-Smith, KS Harris, CJR Bataille, et al. 2024. “Lead Optimisation of OXS007417: in Vivo PK Profile and HERG Liability Modulation to Optimise a Small Molecule Differentiation Agent for the Potential Treatment of Acute Myeloid Leukaemia †.” RSC Medicinal Chemistry 15: 3495–3506.
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Files:: Cogswell_et_al_2024_Lead_optimisation_of.pdf

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Publisher copy:: 10.1039/d4md00275j

Authors

+ Cogswell, TJ More by this author

Institution:: University of Oxford
Division:: HUMS
Department:: Classics Faculty
Sub department:: Chemistry Research Laboratory
Role:: Author

+ Josa-Culleré, L More by this author

Institution:: University of Oxford
Division:: HUMS
Department:: Classics Faculty
Sub department:: Chemistry Research Laboratory
Role:: Author
ORCID:: 0000-0002-3275-9025

+ Zimmer, D More by this author

Institution:: University of Oxford
Division:: HUMS
Department:: Classics Faculty
Sub department:: Chemistry Research Laboratory
Role:: Author

+ Galan, SRG More by this author

Institution:: University of Oxford
Division:: HUMS
Department:: Classics Faculty
Sub department:: Chemistry Research Laboratory
Role:: Author
ORCID:: 0000-0002-6241-0238

+ Jay-Smith, M More by this author

Institution:: University of Oxford
Division:: HUMS
Department:: Classics Faculty
Sub department:: Chemistry Research Laboratory
Role:: Author

More authors...

+ Medical Research Council More from this funder

Funder identifier:: https://ror.org/03x94j517

Publisher:: Royal Society of Chemistry
Journal:: RSC Medicinal Chemistry More from this journal
Volume:: 15
Pages:: 3495-3506
Publication date:: 2024-07-22
Acceptance date:: 2024-07-14
DOI:: 10.1039/d4md00275j
EISSN:: 2632-8682

Language:: English
Pubs id:: 2021936
Local pid:: pubs:2021936
Source identifiers:: 2224424
Deposit date:: 2024-08-29

Terms of use

Copyright holder:: Cogswell et al
Copyright date:: 2024
Rights statement:: © The Royal Society of Chemistry 2024. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Licence:: CC Attribution (CC BY) 3.0

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