Federico Bernal, Ph.D.

Investigator

Laboratory of Protein Dynamics and Signaling

NCI/CCR

Building 560, Room 22-96B
Frederick, MD 21702

301-846-6723

bernalf@mail.nih.gov

Research Topics

The development of therapeutics has evolved significantly over the course of the last two decades with significant efforts geared towards the identification of treatments that selectively target a specific signaling pathway while bearing minimal off-target effects. Protein-protein interactions ultimately govern the vast majority of cellular functions, and an understanding of the molecular interactions occurring within multiprotein complexes is critical for the design and production of inhibitors targeting a specific pathway. The assembly of protein complexes relies heavily on a pre-determined three-dimensional arrangement of atoms; and, in many instances, the interactions take place across extended surfaces devoid of binding pockets, making them inaccessible to small molecules.

Our lab makes use of stapled peptides to target interactions mediated by alpha-helical interfaces. Stapled peptides are hydrocarbon-constrained alpha helices which have emerged as a class of molecular probes and therapeutices capable of targeting molecular pathways with a high degree of selectivity both in vitro and in vivo. Given their ease of synthesis and their drug-like properties, our group has focused on targeting signaling systems ranging from protein-protein interactions relevant in cancer such as the linear ubiquitin assembly chain complex (LUBAC). More recently we have shifted our focus to develop compounds that target protein-DNA interaction, and this foray has led us to the study of transcription factor interactions in bacterial and eukaryotic systems. We have embarked on a study of the bacterial transcription factor sigma-54, which is responsible for the pathogenicity of several disease-causing bacteria, and we are currently testing compounds that target the interaction between sigma-54 and its promoters. Finally, we have expanded our reach by targeting molecular machines involved in the viral infection process, and to this end, we are developing inhibitors against filoviruses and flaviviruses in collaboration with the NIAID Integrated Research Facility.

Biography

Dr. Bernal did his undergraduate training at the Massachusetts Institute of Technology graduating in 1997 with degrees in chemistry and chemical engineering. He obtained his Ph.D. from The Scripps Research Institute in 2002 after performing work on the development of synthetic methodologies for the construction of complex marine natural products in the laboratory of K. C. Nicolaou. Dr. Bernal then returned to Cambridge, MA to undergo postdoctoral training in chemical biology at Harvard University in the group of Gregory L. Verdine. He then continued his foray into cancer chemical biology in the laboratory of Loren D. Walensky at the Dana-Farber Cancer Institute. He established his laboratory in the Metabolism Branch (now the Lymphoid Malignancies Branch) of the Center for Cancer Research at NCI in 2010 and subsequently moved in 2014 to the Laboratory of Protein Dynamics and Signaling in Frederick, MD. His research focus involves the investigation and manipulation of disease pathways with synthetic molecules.

Selected Publications

  1. Yang Y, Schmitz R, Mitala J, Whiting A, Xiao W, Ceribelli M, Wright GW, Zhao H, Yang Y, Xu W, Rosenwald A, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Wiestner A, Kruhlak MJ, Iwai K, Bernal F, Staudt LM. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discov. 2014;4(4):480-93.

  2. de Lange J, Teunisse AF, Vries MV, Lodder K, Lam S, Luyten GP, Bernal F, Jager MJ, Jochemsen AG. High levels of Hdmx promote cell growth in a subset of uveal melanomas. Am J Cancer Res. 2012;2(5):492-507.

  3. Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18(8):1239-47.

  4. Pitter K, Bernal F, Labelle J, Walensky LD. Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008;446:387-408.

  5. Bernal F, Wade M, Godes M, Davis TN, Whitehead DG, Kung AL, Wahl GM, Walensky LD. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. 2010;18(5):411-22.


This page was last updated on June 15th, 2017