Methods to improve inhibitors targeted to EGFR kinase

• Project/Area Number: 23870041
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Structural biochemistry
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: PARKER Lorien 独立行政法人理化学研究所, システム研究チーム, 研究員 (60604999)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Crystallography / Rational Drug Design / kinase inhibitor / Resistant mutants / EGFR Kinase / GAK / AMP Kinase

Research Abstract

We developed an AMP-kinase inhibitor through three rounds of optimization from a non-specific compound through to a specific and potent compound using structure guided drug design. For GAK significantly larger and more reproducible crystals were obtained but diffraction is still limited to 8Å. Further optimization of crystallization conditions is underway. Despite optimization, the EGFR kinase complexes did not show any electron density for the inhibitors. Currently, a new set of inhibitors, identified in 2013, through in silico screening using our double mutant AMP-PNP structure, have just entered crystallization trials.

Research Products

• [Journal Article] Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor (2013)
  • Author(s): Seiko Yoshikawa, Mutsuko Kukimoto-Niino, Lorien Parker, Noriko Handa, Takaho Terada, Takako Fujimoto, Yumiko Terazawa, Motoaki Wakiyama, Masaru Sato, Satoshi Sano, Tomoyuki Kobayashi, Tetsuo Tanaka, Lirong Chen, Zhi-jie Liu, Bi-cheng Wang, Mikako Shirouzu, Seiji Kawa, Kentaro Semba, Tadashi Yamamoto and Shigeyuki Yokoyama
  • Journal Title: Oncogene Volume: 32 (1) Pages: 27-38
  • Peer Reviewed
• [Journal Article] Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor (2012)
  • Author(s): Lorien Parker, Hisami Watanabe, Keiko Tsuganezawa, Yuri Tomabechi, Noriko Handa, Mikako Shirouzu, Hitomi Yuki, Teruki Honma, Naoko Ogawa, Tetsuo Nagano, Shigeyuki Yokoyama and Akiko Tanaka
  • Journal Title: Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. Volume: 68 (8) Pages: 860-866
  • Peer Reviewed
• [Journal Article] Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound (2012)
  • Author(s): Hirofumi Nakano, Nae Saito, Lorien Parker, Yukio Tada, Masanao Abe, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Takayoshi Okabe and Tetsuo Nagano
  • Journal Title: J. Med. Chem. Volume: 55 (11) Pages: 5151-5164
  • Peer Reviewed
• [Journal Article] A novel pim-1 kinase inhibitor targeting residues that bind the substrate peptide (2012)
  • Author(s): Keiko Tsuganezawa, Hisami Watanabe, Lorien Parker, Hitomi Yuki, Shigenao Taruya, Yukari Nakagawa, Daisuke Kamei, Masumi Mori, Naoko Ogawa, Yuri Tomabechi, Noriko Handa, Teruki Honma, Shigeyuki Yokoyama, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano and Akiko Tanaka
  • Journal Title: J. Mol. Biol. Volume: 417 (3) Pages: 240-252
  • Peer Reviewed
• [Journal Article] Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor (2012)
  • Author(s): Seiko Yoshikawa, Mutsuko Kukimoto-Niino, Lorien Parker, 他
  • Journal Title: Oncogene Volume: (In press)
  • Peer Reviewed
• [Presentation] Discovery of a potent and selective Pim1 inhibitor by rational compound evolution (2012)
  • Author(s): Nakano, H., Saito, N., Parker, L., Tada, Y., Abe, M., Tsuganezawa, K., Yokoyama, S., Tanaka, A., Kojima, H., Okabe, T. and Nagano, T.
  • Organizer: EFMC-ISMC2012 22nd International Symposium on Medicinal Chemistry
  • Place of Presentation: Berlin, Germany.
• [Presentation] DISCOVERY OF A POTENT AND SELECTIVE PIM1 INHIBITOR BY RATIONAL COMPOUND EVOLUTION (2012)
  • Author(s): Nakano, H.
  • Organizer: EFMC-ISMC2012 22nd International Symposium on Medicinal Chemistry
  • Place of Presentation: Berlin, Germany
• [Presentation] Structural studies of Pim-1 kinase inhibitors (2011)
  • Author(s): Parker, L., Handa, N., Tomabechi, Y., Shirouzu, M., Tsuganezawa, K., Honma, T., Yuki, H., Tanaka, A. and Yokoyama, S.
  • Organizer: Anticancer Drugs 2011
  • Place of Presentation: Stockholm, Sweden.
• [Presentation] Structural studies of Pim-1 kinase inhibitors (2011)
  • Author(s): Parker, L., Handa, N., Shirouzu, M., Tsuganezawa, K., Honma, T., Yuki, H., Tanaka, A. and Yokoyama, S.
  • Organizer: XXII Congress and General Assembly of the International Union of Crystallography(IUCr)
  • Place of Presentation: Madrid, Spain.
• [Presentation] Structural studies Of Pim-1 Kinase inhibitors (2011)
  • Author(s): Lorien Parker
  • Organizer: Anti-Cancer Drugs
  • Place of Presentation: Stockholm, Sweden
• [Remarks] X線結晶構造解析の情報を基礎に抗がん剤の開発へーロリエン・ジェーン・パーカー客員研究員
  • URL: http://www.riken.jp/~/media/riken/pr/publications/annual_report/annual_report-2011_12-jp.pdf