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Sci Transl Med. 2019 Mar 20;11(484). pii: eaar5012. doi: 10.1126/scitranslmed.aar5012.

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

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Peptomyc S.L., Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Syros Pharmaceuticals, Cambridge, MA 02139, USA.
Département de Biochimie, PROTÉO and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, 28040, Spain.
Peptomyc S.L., Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, 08010, Spain.
Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, 08193 , Spain.


Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.

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