1403865-19-9Relevant articles and documents
Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001
Nagy, Mark A.,Hilgraf, Robert,Mortensen, Deborah S.,Elsner, Jan,Norris, Stephen,Tikhe, Jayashree,Yoon, Won,Paisner, David,Delgado, Mercedes,Erdman, Paul,Haelewyn, Jason,Khambatta, Godrej,Xu, Li,Romanow, William J.,Condroski, Kevin,Bahmanyar, Sogole,McCarrick, Meg,Benish, Brent,Blease, Kate,Lebrun, Laurie,Moghaddam, Mehran F.,Apuy, Julius,Canan, Stacie S.,Bennett, Brydon L.,Satoh, Yoshitaka
supporting information, p. 18193 - 18208 (2021/12/27)
As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).
CYCLIN-DEPENDENT KINASE INHIBITORS
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Page/Page column 271, (2020/07/15)
Described herein are compounds and their pharmaceutically acceptable salts, pharmaceutical compositions thereof, methods of treatment, and medical uses. The compounds described herein are modulators of cyclin-dependent kinases, and are useful in the treatment or alleviation of protein kinase associated disorders, including cancer, infectious diseases, autoimmune diseases, or cardiovascular diseases.
