1. Academic Validation
  2. Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma

Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma

  • Mol Cancer Ther. 2023 Mar 2;22(3):317-332. doi: 10.1158/1535-7163.MCT-22-0306.
Kohei Takano 1 Yoichi Munehira 1 Mana Hatanaka 1 Ryo Murakami 1 Yoshihiro Shibata 2 Takeshi Shida 2 Kosuke Takeuchi 2 Sho Takechi 2 Toshiki Tabata 3 Takashi Shimada 4 Shuhei Kishikawa 4 Yumi Matsui 5 Osamu Ubukata 5 Takahiko Seki 6 Yasuyuki Kaneta 1
Affiliations

Affiliations

  • 1 Oncology Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 2 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 3 Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 4 Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • 5 Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • 6 Early Clinical Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Abstract

Patients with melanoma with activating BRaf mutations (BRaf V600E/K) initially respond to combination therapy of BRaf and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRaf gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK Inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRaf Inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK Inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164474
    MEK抑制剂
    MEK