Structure-based design yields peptidomimetic APC–ARM pocket inhibitors that block Asef binding.

  • Major finding: Structure-based design yields peptidomimetic APC–ARM pocket inhibitors that block Asef binding.

  • Approach: Targeting the APC–Asef interaction prevents Asef-mediated activation of CDC42, disrupting cell migration.

  • Impact: Inhibition of the APC–Asef interaction may potentially suppress colorectal cancer metastasis.

Asef is a guanine nucleotide exchange factor that specifically activates the small Rho-like GTPases, including CDC42 and RAC1, to promote cell migration. APC binding alleviates the negative regulation of Asef, resulting in aberrant migration of colorectal cancer cells. Thus, the APC–Asef interaction is a potential therapeutic target to disrupt invasive migration in colorectal cancer, but pharmacologic agents that target this interaction are not available. Jiang, Deng, Yang, and colleagues used structure-based drug design to generate peptidomimetic inhibitors that bind to APC to block Asef binding. Asef binds to the ARM domain of APC, and truncated peptides were screened for binding to the APC–Asef interaction hotspot. MAI-005 was the best inhibitor of the APC–Asef interactions, and further optimization including determination of crystal structures and use of cellular assays yielded the more potent inhibitors MAI-150 and MAI-203. These inhibitors bound to the APC–ARM pocket and induced conformation changes in Arg549, Lys586, and Gln542. The inhibitors were conjugated to the transcription trans-activating (TAT) sequence of HIV to improve cell penetration, and, in HEK293T cells, the TAT conjugated compounds MAIT-150 and MAIT-203 directly targeted APC to disrupt the APC–Asef interaction in a dose-dependent manner, with MAIT-203 having the most potent effects. Further, in the colorectal cancer cell lines SW480 and HCT116, the MAIT compounds suppressed cell migration and invasion, but did not affect proliferation or cell morphology. Mechanistically, MAIT-203 prevented CDC42 activation, but not RAC1 activation, indicating that APC promotes cell migration via Asef-mediated activation of CDC42. The design of the first-in-class peptidomimetic inhibitors of the APC–Asef interaction suggests that therapeutic targeting may be feasible, and supports further in vivo testing of these compounds to determine their efficacy in suppressing metastasis in colorectal cancer.

Jiang H, Deng R, Yang X, Shang J, Lu S, Zhao Y, et al. Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration. Nat Chem Biol 2017 Jul 24 [Epub ahead of print].

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