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.
Thomas J CogswellLaia Josa-CulleréDavid ZimmerSébastien R G GalanMorgan Jay-SmithKatrina S MaddenCarole J R BatailleThomas R JacksonDouzi ZhangStephen G DaviesParesh VyasThomas A MilneGraham M WynneAngela J RussellPublished in: RSC medicinal chemistry (2024)
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.
Keyphrases
- small molecule
- end stage renal disease
- acute myeloid leukemia
- chronic kidney disease
- induced apoptosis
- ejection fraction
- newly diagnosed
- liver failure
- oxidative stress
- peritoneal dialysis
- bone marrow
- prognostic factors
- cell cycle arrest
- drug induced
- cell proliferation
- signaling pathway
- respiratory failure
- acute lymphoblastic leukemia
- cell death
- protein protein
- climate change
- atomic force microscopy
- extracorporeal membrane oxygenation
- single molecule
- amino acid