2. Academic Validation
  3. Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

  • Bioorg Med Chem. 2024 Mar 15:102:117674. doi: 10.1016/j.bmc.2024.117674.
Hikaru Fujita 1,  Sachiko Arai 2,  Hiroshi Arakawa 3,  Kana Hamamoto 3,  Toshiyuki Kato 3,  Tsubasa Arai 3,  Nanaka Nitta 3,  Kazuki Hotta 3,  Natsuko Hosokawa 4,  Takako Ohbayashi 4,  Chiaki Takahashi 2,  Yasuhide Inokuma 5,  Ikumi Tamai 3,  Seiji Yano 2,  Munetaka Kunishima 6,  Yoshihiro Watanabe 7
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: [email protected].
  • 2 Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
  • 3 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 4 Department of Rheumatology, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
  • 5 Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido, 060-8628 Japan; Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Kita 21, Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0021 Japan.
  • 6 Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan. Electronic address: [email protected].
  • 7 Innovative Clinical Research Center, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan. Electronic address: [email protected].
PMID: 38457912 DOI: 10.1016/j.bmc.2024.117674
Abstract

Controlling Ras mutant Cancer progression remains a significant challenge in developing Anticancer drugs. Whereas Ras G12C-covalent Binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras Binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug-drug conjugates (DDCs) by combining the MEK Inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. The DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic Enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and Anticancer efficacies comparable to those of trametinib. The PK profiles of trametinib and the Akt Inhibitor were unified through the DDC formation. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers.

Keywords

Akt inhibitor; Downstream signal; Linker; RAS-mutations; Trametinib; drug–drug conjugate (DDC).

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