Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein

Abstract

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAFV600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAFV600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC50 values in the 40–88 nM range. Selected compounds inhibited BRAFV600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.

Navigating the ERK1/2 MAPK Cascade

“…Another BRAFV600E-selective PROTAC, CRBN(BRAF)-24, was based on PLX8394 [532]. In parallel, encorafenib-based PROTACs were developed but none of them resulted in degradation of the mutant BRAF, probably due to failure to recruit the ubiquitin ligase [533].…”

Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo

“…PROTAC, degrading the entire protein to eliminate both enzymatic activity and nonenzymatic kinase functions, has a unique advantage over traditional small-molecule drugs against resistance. − Till now, a few of SOS1 degraders have been disclosed, such as degrader S4 , S5 , and S6 (Figure ). The degrader S4 achieved up to 92% SOS1 degradation in both CRC cell lines and PDOs and could inhibit KRAS G12A CRC organoid viability with a moderate IC 50 of 480 nM .…”

PROTACs: A novel strategy for cancer drug discovery and development

“…[19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years. 5,8,19,[42][43][44][45] At the present, more than 10 PROTAC degraders have entered clinical Phase I-II trials with ARV-471 and ARV-110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively.…”

“…TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

“… 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 …”