Antitumor Activity of LB42907, a Potent and Selective Farnesyltransferase Inhibitor: Synergistic Effect in Combination with Other Anticancer Drugs

Bulletin of the Korean chemical society

Dong-Myung Kim¹  Jong Sung Koh¹  Hyun-Ho Chung¹  Semi Kim¹  Joonghoon Park¹  Ji Hyun Park¹  Jinho Lee¹  Kwihwa Kim¹  Heung-Soo Cho¹  Shin Wu Jeong¹  Sun-Young Koo¹  Hyeon Joo Yim¹ 

关键词: Farnesyltransferase inhibitor;    LB42907;    Antitumor activity;    Xenograft;    Combination effect;   

DOI  :  

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

Inhibitors of farnesyltransferase (FT), a key enzyme in the post-translational modifications of Ras proteins, have been extensively studied as novel anticancer agents in the preclinical stages, some of which are currently in clinical development. Previously, it has been reported that a novel FT inhibitor LB42907 inhibits Ras farnesylation in the nanomolar range in vitro. The aim of this study was to assess the antitumor efficacy of LB42907 in vitro and in vivo. Anchorage-independent growth of various human tumor cell lines was potently inhibited by treatment with LB42907, comparable to other FT inhibitors in clinical development. In the nude mouse, oral administration of LB42907 demonstrated potent antitumor activity in several human tumor xenograft models including bladder, lung and pancreas origin. Interestingly, significant tumor regression in EJ (bladder) and A549 (lung) xenografts was induced by LB42907 treatment. The effectiveness of LB42907 was also investigated in simultaneous combination with paclitaxel, vincristine, cisplatin or gemcitabine against NCI-H460, A549, and HCT116 cells in vitro using median-effect analysis. LB42907 markedly synergized with most anticancer drugs tested in this study in NCI-H460 cell. In contrast, LB42907 displayed antagonism or partial synergism with these drugs in A549 and HCT116 cells, depending on the class of combined drugs and/ or the level of cytotoxicity. Our results demonstrate that LB42907 is an effective antitumor agent in vitro and in vivo and combination of LB42907 with other chemotherapeutic drugs results in synergistic or antagonistic effects mainly in a cell line-dependent manner. Further preclinical study is warranted.

【 授权许可】

Unknown