ODM-201 is a potent antagonist of the androgen receptor (AR) with a Ki value of 11nM and an IC50 value of 26nM [1]. ODM-201 maintains the binding conformation in the F877L-mutated pocket through hydrogen and Van der Waals interactions, inhibiting transcriptional activity of AR mutants [2]. ODM-201 has been widely used in preclinical models to inhibit the progression of prostate cancer[3].
In vitro, ODM-201 treatment for 6 days significantly inhibited the viability of LNCaP/AR cells, with an IC50 value of 1.65µM[4]. Treatment with 10µM ODM-201 for 72 hours significantly inhibited the growth of C4-2 cells and induced cellular senescence, down-regulating the mRNA level of CDKN2A and the protein level of p16[5]. Treatment with 30µM ODM-201 for 4 days significantly reduced the expression of cyclin D1 in BT-549 cells, upregulated the phosphorylation of ERK, and inhibited cell proliferation[6].
In vivo, ODM-201 treatment via intraperitoneally injection at a dose of 20mg/kg/day for 14 days inhibited the tumor growth in mice with LNCaP cell xenografts[7]. Oral administration of 100mg/kg dose of ODM-201 daily for 2 months significantly inhibited tumor growth in the xenograft mouse model of KuCaP-1 prostate cancer carrying the AR W742C mutation, with limited weight loss[8].
References:
[1] Moilanen A M, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies[J]. Scientific reports, 2015, 5(1): 12007.
[2] Borgmann H, Lallous N, Ozistanbullu D, et al. Moving towards precision urologic oncology: targeting enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor using the novel inhibitor darolutamide (ODM-201)[J]. European urology, 2018, 73(1): 4-8.
[3] Bastos D A, Antonarakis E S. Darolutamide for castration-resistant prostate cancer[J]. OncoTargets and therapy, 2019: 8769-8777.
[4] Yu J, Zhou P, Hu M, et al. Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants[J]. European journal of medicinal chemistry, 2019, 182: 111608.
[5] Gupta S, Pungsrinont T, Ženata O, et al. Interleukin-23 represses the level of cell senescence induced by the androgen receptor antagonists enzalutamide and darolutamide in castration-resistant prostate cancer cells[J]. Hormones and Cancer, 2020, 11(3): 182-190.
[6] Kuroiwa Y, Ito K, Nakayama J, et al. Analysis of the responsiveness to antiandrogens in multiple breast cancer cell lines[J]. Genes to Cells, 2024, 29(4): 301-315.
[7] Li B, Cheng B, Huang H, et al. Darolutamide-mediated phospholipid remodeling induces ferroptosis through the SREBP1-FASN axis in prostate cancer[J]. International journal of biological sciences, 2024, 20(12): 4635.
[8] Sugawara T, Baumgart S J, Nevedomskaya E, et al. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models[J]. International journal of cancer, 2019, 145(5): 1382-1394.
ODM-201是一种强效的雄激素受体拮抗剂，Ki值为11nM，IC50值为26nM[1]。ODM-201通过氢键和范德华相互作用维持其在F877L突变口袋中的结合构象，从而抑制突变AR的转录活性[2]。ODM-201已被广泛用于临床前模型中抑制前列腺癌的进展[3]。
在体外，ODM-201处理6天显著抑制了LNCaP/AR细胞的活力，IC50值为1.65µM[4]。使用10µM的ODM-201处理C4-2细胞72小时，显著抑制了细胞生长并诱导了细胞衰老，下调了CDKN2A的mRNA水平和p16的蛋白水平[5]。使用30µM的ODM-201处理BT-549细胞4天，显著降低了细胞周期蛋白D1的表达，上调了ERK的磷酸化，并抑制了细胞增殖[6]。
在体内，每日腹腔注射20mg/kg剂量的ODM-201，连续14天，抑制了携带LNCaP细胞异种移植瘤小鼠的肿瘤生长[7]。每日口服100mg/kg剂量的ODM-201，连续2个月，显著抑制了携带AR W742C突变的KuCaP-1前列腺癌异种移植小鼠模型中的肿瘤生长，且体重减轻有限[8]。