Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 6, Issue 12, Pages 1241-1246Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00398
Keywords
Kinase inhibitor; oncology; hERG; pK(a)
Categories
Funding
- NIH
- NIGMS
- Howard Hughes Medical Institute
- Office of Basic Energy Sciences of the U.S. Department of Energy [DE-AC02-05CH11231]
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Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK(a) and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.
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