Dual mechanism MAPK inhibitors bind MAPKs

Stable Identifier
Reaction [binding]
Homo sapiens
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A number of 'dual mechanism' MAPK inhibitors are in preclinical or clinical trials (reviewed in Roskoski, 2019). Dual mechanism inhibitors, including the ATP-competitive inhibitors SCH772984 and MK-8353, bind to the unphosphorylated MAPK and prevent both its own kinase activity and its phosphorylation by MAP2Ks (Morris et al, 2013; Deng et al 2014; Chaikuad et al, 2014; Boga et al, 2018; Moschos et al, 2019; reviewed in Samatar and Poulikakos, 2014). MAPK inhibitors offer the potential to mitigate the development of resistance to RAF and MAP2K inhibitors, which often involves reactivation of MAPK-dependent signaling. As a result, MAPK inhibitors are frequently used in combination with RAF and MAP2K-directed therapeutics (reviewed in Samatar and Poulikakos, 2014; Roskoski, 2019).

Literature References
PubMed ID Title Journal Year
30034615 MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

Alhassan, AB, Paliwal, S, Desai, J, Dayananth, P, Zhu, H, Samatar, AA, Kelly, J, Long, B, Doll, R, Sun, R, Sherborne, B, Yao, X, Mei, H, Hesk, D, Cox, K, Shipps, GW, Muppalla, K, Shih, NY, Zhang, LK, Deng, Y, Patel, M, Xiao, L, Boga, SB, Bishop, R, Liu, G, Nan, Y, Windsor, WT, Hruza, AW, Buevich, A, Tsui, HC, Taylor, SA, Gudipati, S, Wang, T, Zhu, L, Wang, J, Kirschmeier, P, Black, S, Jin, W, Cooper, AB, Carr, D, Gao, X

ACS Med Chem Lett 2018
25195011 A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics

Liang, Y, Knapp, S, Chaikuad, A, Tacconi, EM, Zimmer, J, Gray, NS, Tarsounas, M

Nat. Chem. Biol. 2014
23614898 Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors

Liu, J, Fawell, S, Angagaw, MH, Paliwal, S, Zawel, L, Desai, J, Jha, S, Pinheiro, EM, Zhang, L, Dayananth, P, Restaino, CR, Hicklin, D, Shipps, G, Jayaraman, L, Morris, EJ, Zhu, H, Samatar, AA, Babu, BS, Witter, D, Long, B, Cooper, A, Windsor, W, Siliphaivanh, P, Xiao, L, Pelletier, MR, Zhang, R, Gilliland, DG, Zhu, L, Zhao, S, Philippar, U, Hruza, A, Deng, Y, Kelly, J, Wang, J, Kirschmeier, P, Dinunzio, E, Daublain, P, Black, S, Jin, W, Carr, D, Lutterbach, BA, Gao, X, Bishop, WR

Cancer Discov 2013
30794926 Targeting ERK1/2 protein-serine/threonine kinases in human cancers

Roskoski, R Jr

Pharmacol. Res. 2019
25313996 Discovery of novel, dual mechanism ERK inhibitors by affinity selection screening of an inactive kinase

English, JM, Nan, Y, Dayananth, P, Zhu, HY, Chuang, CC, Windsor, WT, Annis, DA, Hruza, AW, Samatar, AA, Wang, T, Kirschmeier, P, Cooper, A, Jin, W, Shipps, GW, Carr, D, Deng, Y, Xiao, L

J. Med. Chem. 2014
29467321 Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Moreno, BH, Schiller, J, Long, BJ, Sullivan, RJ, Rubino, J, Dayananth, P, Chun, P, Tawbi, HA, Hwu, WJ, Samatar, AA, Flaherty, KT, Miselis, NR, Cooper, A, Shipps, GW, Fong, PC, Deng, Y, Ramanathan, RK, Robert, L, Shapira-Frommer, R, Rush, TS, Ribas, A, Rubin, EH, Kirschmeier, P, Adjei, AA, Zhang, D, Carr, D, Moschos, SJ, Bishop, WR

JCI Insight 2018
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Poulikakos, PI, Samatar, AA

Nat Rev Drug Discov 2014
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