Discovery of spiro amide SHR902275: A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers

Zhao, Peng; Zhuang, Liujing; Wang, Xiangzhu; Huang, Song; Wu, Heping; Zhou, Yu; Yan, Yuna; Zhang, Fan; Shen, Ru; Li, Jing; Liu, Suxing; Zhang, Rumin; Dong, Ping; Mao, Yuchang; Fan, Yuanmin; He, Chao; Sun, Jiakang; Zhang, Lei; Hu, Qiyue; Wan, Hong; Feng, Jun; Bai, Chang; He, Feng; Tao, Weikang

doi:10.1016/j.ejmech.2021.114040

Cited by 8 publications

(1 citation statement)

References 23 publications

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“…The selective CRAF inhibitor ZM336372 significantly reduces bioactive hormone levels and human achaete-scute homologue-1 (ASH-1) expression in carcinoid tumor cells, leading to pronounced suppression of cellular proliferation and the cell cycle [ 25 ]. Recently, Zhao et al identified a novel spirocyclic CRAF inhibitor, SHR902275, which has exhibited excellent drug metabolism and pharmacokinetic properties in vivo [ 26 ]. GW5074, a CRAF inhibitor, was found to enhance the anticancer effects of sorafenib by inducing mitochondrial dysfunction [ 22 , 23 ].…”

Section: Combination Therapy and Related Anti-tumor Applicationsmentioning

confidence: 99%

Targeting CRAF kinase in anti-cancer therapy: progress and opportunities

Wang,

Laster,

Jia

et al. 2023

Mol Cancer

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The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.

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