DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen

Nishikawa, ShigetoKaida, AtsushiParrales, AlejandroRanjan, AtulAlalem, MohamedRen, HongyiSchoenen, Frank J.Johnson, David K.Iwakuma, Tomoo2023-02-132023-02-132022-10-31Nishikawa, S., Kaida, A., Parrales, A. et al. DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen. Cell Death Discov. 8, 437 (2022). https://doi.org/10.1038/s41420-022-01229-5https://hdl.handle.net/1808/33779Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and preventing mutp53 from proteasomal degradation. However, strategies to deplete mutp53 are not well-established, and no HSP40/JDPs inhibitors are clinically available. To identify compounds that bind to DNAJA1 and induce mutp53 degradation, we performed an in silico docking study of ~10 million of compounds from the ZINC database for the J-domain of DNAJA1. A compound 7-3 was identified, and its analogue A11 effectively reduced the levels of DNAJA1 and conformational mutp53 with minimal effects on the levels of wild-type p53 and DNA-contact mutp53. A11 suppressed migration and filopodia formation in a manner dependent on DNAJA1 and conformational mutp53. A mutant DNAJA1 with alanine mutations at predicted amino acids (tyrosine 7, lysine 44, and glutamine 47) failed to bind to A11. Cells expressing the mutant DNAJA1 became insensitive to A11-mediated depletion of DNAJA1 and mutp53 as well as A11-mediated inhibition of cell migration. Thus, A11 is the first HSP40/JDP inhibitor that has not been previously characterized for depleting DNAJA1 and subsequently conformational mutp53, leading to inhibition of cancer cell migration. A11 can be exploited for a novel treatment against cancers expressing conformational mutp53.© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License.http://creativecommons.org/licenses/by/4.0/Drug developmentTumour-suppressor proteinsDNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screenArticle10.1038/s41420-022-01229-5https://orcid.org/0000-0003-2626-295Xhttps://orcid.org/0000-0003-4262-8173https://orcid.org/0000-0001-7249-7958PMC9622836openAccess