Reactome | Dual mechanism MAPK inhibitors bind MAPKs

Dual mechanism MAPK inhibitors bind MAPKs

Stable Identifier

R-HSA-9657603

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

5/5

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Dual mechanism MAPK inhibitors bind MAPKs

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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