6WU8

Structure of human SHP2 in complex with inhibitor IACS-13909

Summary for 6WU8

• Entry DOI: 10.2210/pdb6wu8/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (3 entities in total)
• Functional Keywords: phosphatase, inhibitor, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 123737.34

Authors

Leonard, P.G.,Joseph, S.,Rodenberger, A. (deposition date: 2020-05-04, release date: 2021-03-17, Last modification date: 2023-10-18)

Primary citation

Sun, Y.,Meyers, B.A.,Czako, B.,Leonard, P.,Mseeh, F.,Harris, A.L.,Wu, Q.,Johnson, S.,Parker, C.A.,Cross, J.B.,Di Francesco, M.E.,Bivona, B.J.,Bristow, C.A.,Burke, J.P.,Carrillo, C.C.,Carroll, C.L.,Chang, Q.,Feng, N.,Gao, G.,Gera, S.,Giuliani, V.,Huang, J.K.,Jiang, Y.,Kang, Z.,Kovacs, J.J.,Liu, C.Y.,Lopez, A.M.,Ma, X.,Mandal, P.K.,McAfoos, T.,Miller, M.A.,Mullinax, R.A.,Peoples, M.,Ramamoorthy, V.,Seth, S.,Spencer, N.D.,Suzuki, E.,Williams, C.C.,Yu, S.S.,Zuniga, A.M.,Draetta, G.F.,Marszalek, J.R.,Heffernan, T.P.,Kohl, N.E.,Jones, P.
Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.
Cancer Res., 80:4840-4853, 2020

PubMed Abstract: Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation and caused tumor regression . Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

PubMed: 32928921
DOI: 10.1158/0008-5472.CAN-20-1634

Experimental method

X-RAY DIFFRACTION (2.4 Å)