Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001

by Selleckchem | Aug 06 2023

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).

Comments:

This manuscript describes the synthesis and structure-activity relationship (SAR) studies of a new series of JNK inhibitors aimed at increasing JNK1 bias, based on emerging biological data suggesting the involvement of JNK1 in fibrosis pathology. The goal was to identify compounds with improved JNK1 selectivity compared to the clinical compound tanzisertib (CC-930).

The researchers focused on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides and performed SAR optimization. Through this process, they identified compounds that displayed potent JNK inhibitory activity in the low nanomolar range. These compounds also demonstrated overall kinome selectivity, indicating a favorable specificity profile.

In addition to their inhibitory potency, the compounds were evaluated for their ability to inhibit the phosphorylation of c-Jun, a direct substrate of JNK. The results showed that the identified compounds effectively inhibited c-Jun phosphorylation in cellular assays, further supporting their potential as JNK inhibitors.

Furthermore, the researchers optimized the physicochemical properties of the compounds to ensure favorable drug-like characteristics. This optimization led to the development of compounds that exhibited excellent systemic exposure following oral administration. This crucial characteristic enabled further in vivo efficacy studies.

Among the compounds synthesized and evaluated, a candidate molecule with the designation CC-90001 was selected for clinical development. CC-90001 demonstrated promising properties, including potent JNK inhibition, good kinome selectivity, and the ability to inhibit c-Jun phosphorylation. As a result, CC-90001 has progressed to Phase II clinical trials in patients with idiopathic pulmonary fibrosis (NCT03142191).

These findings highlight the successful identification and optimization of JNK inhibitors with increased JNK1 bias, leading to the selection of CC-90001 as a potential therapeutic candidate for the treatment of fibrotic disorders.