Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor

Jung-Hoon Lee, Eunji Kang, Jungmin Lee, Jungmin Kim, Kyoung Hu Lee, Jieun Han, Hye Yoon Kang, Soshin Ahn, Youngmi Oh, Dongkyu Shin, Kyeyeon Hur, Su Young Chae, Paul H. Song, Yong-In Kim, Jae Chan Park () and Jae Il Lee ()
Additional contact information
Jung-Hoon Lee: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Eunji Kang: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Jungmin Lee: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Jungmin Kim: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Kyoung Hu Lee: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Jieun Han: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Hye Yoon Kang: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Soshin Ahn: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Youngmi Oh: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Dongkyu Shin: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Kyeyeon Hur: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Su Young Chae: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Paul H. Song: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Yong-In Kim: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Jae Chan Park: Bio Research Center, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.
Jae Il Lee: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd.

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer.

Date: 2014
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DOI: 10.1038/ncomms4814

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