Ridaforolimus (Deforolimus, MK-8669) is an orally active and selective Mammalian Target of Rapamycin (mTOR) inhibitor (IC₅₀=0.2nM), Ridaforolimus acts by inhibiting the mTOR signaling pathway, thereby affecting the phosphorylation of downstream effector proteins such as S6 and 4E-BP1[1-2]. By suppressing mTOR activity, Ridaforolimus significantly inhibits tumor cell proliferation[3-4].
In vitro, treatment of prostate cancer cell lines (LNCaP and C4-2) with Ridaforolimus (0.5–50nM) for 1–3 days significantly reduces cell proliferation and induces G₁ phase cell cycle arrest via inhibition of the mTOR signaling pathway[5]. Ridaforolimus (0–1000nM) treatment for 72 hours markedly suppresses the proliferation rate of sarcoma and endometrial cancer cell lines[6].
In vivo, Ridaforolimus (1mg/kg) administered via intraperitoneal injection on an intermittent schedule (five consecutive days per week) for four weeks significantly inhibits tumor growth and induces tumor regression in nude mice bearing MCF-7/AC-1 xenografts[7]. Daily intraperitoneal injection of Ridaforolimus (1mg/kg) for 22 days in NOD/SCID mice carrying ARK1 and ARK2 uterine serous carcinoma xenografts also leads to significant tumor growth suppression and regression[8].
References:
[1] Ridaforolimus. Drugs R D. 2010;10(3):165-78.
[2] Dancey JE, Monzon J. Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies. Future Oncol. 2011 Jul;7(7):827-39.
[3] Wang L, Qiu Q, Yang D, et al. Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review. Front Pharmacol. 2024 Mar 22;15:1173240.
[4] Spreafico A, Mackay HJ. Current phase II clinical data for ridaforolimus in cancer. Expert Opin Investig Drugs. 2013 Nov;22(11):1485-93.
[5] Squillace RM, Miller D, Wardwell SD, et al. Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models. Int J Oncol. 2012 Aug;41(2):425-32.
[6] Squillace RM, Miller D, Cookson M, et al. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther. 2011 Oct;10(10):1959-68.
[7] Becker MA, Hou X, Tienchaianada P, et al. Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer. 2016 Oct 20;16(1):814.
[8] Hernandez SF, Chisholm S, Borger D, et al. Ridaforolimus improves the anti-tumor activity of dual HER2 blockade in uterine serous carcinoma in vivo models with HER2 gene amplification and PIK3CA mutation. Gynecol Oncol. 2016 Jun;141(3):570-579.
Ridaforolimus (Deforolimus, MK-8669) 是一种口服有效的选择性哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂（IC50=0.2nM），能够通过抑制mTOR信号通路进而影响S6和4E-BP1等下游效应蛋白的磷酸化[1-2]。Ridaforolimus通过抑制mTOR活性对肿瘤细胞增殖产生显著的抑制作用[3-4]。
在体外，Ridaforolimus(0.5–50nM)处理前列腺癌细胞系（如LNCaP和C4-2细胞）1–3天，通过抑制mTOR信号通路显著降低细胞增殖并诱导G1期细胞周期阻滞[5]。Ridaforolimus（0–1000nM）处理肉瘤和子宫内膜癌细胞系72小时，显著抑制细胞增殖率[6]。
在体内，Ridaforolimus（1mg/kg）以每周5天连续给药的间歇方案腹腔注射处理荷有MCF-7/AC-1异种移植瘤的裸鼠，持续4周，显著抑制了肿瘤生长并诱导肿瘤消退[7]。Ridaforolimus（1mg/kg）每日腹腔注射处理携带ARK1和ARK2子宫浆液性癌异种移植瘤的NOD/SCID小鼠，持续22天，显著抑制了肿瘤生长并诱导肿瘤消退[8]。