一种新的细胞周期蛋白依赖性激酶(CDK)9抑制剂QHRD107对急性髓系白血病的临床前疗效

doi:10.5246/jcps.2021.02.012

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (2): 146-156.DOI: 10.5246/jcps.2021.02.012

一种新的细胞周期蛋白依赖性激酶(CDK)9抑制剂QHRD107对急性髓系白血病的临床前疗效

周艳¹, 宋恒文¹, 邵志超¹, 尹博民², 付西美³, 谢典佑³, 韦利军¹^,^*()

1. 常州千红生化制药股份有限公司, 江苏常州 213125
2. 常州英诺升康生物医药科技有限公司, 江苏常州 213125
3. 中国药科大学, 江苏南京 211198

收稿日期:2020-09-11 修回日期:2020-10-15 接受日期:2020-11-08 出版日期:2021-02-28 发布日期:2021-02-27
通讯作者: 韦利军
作者简介:
+ Tel.: +86-519-86020517, E-mail: wljcpu@qhsh.com.cn
基金资助:
Jiangsu Province policy guidance program (International Science and Technology Cooperation)-Overseas Joint laboratory Construction Project (Grant No. BZ2017044); Changzhou Science and Technology Support Plan (Social Development, Grant No. CE20185055).

Preclinical efficacy of a novel cyclin-dependent kinase 9 inhibitor, QHRD107 against acute myeloid leukemia

Yan Zhou¹, Hengwen Song¹, Zhichao Shao¹, Bomin Yin², Ximei Fu³, Dianyou Xie³, Lijun Wei¹^,^*()

1 Changzhou Qianhong Bio-pharma Co Ltd., Jiangsu 213125, China
2 Changzhou Le Sun Pharmaceuticals Co., Ltd., Jiangsu 213125, China
3 China Pharmaceutical University, Jiangsu 211198, China

Received:2020-09-11 Revised:2020-10-15 Accepted:2020-11-08 Online:2021-02-28 Published:2021-02-27
Contact: Lijun Wei

摘要/Abstract

摘要：

QHRD107是细胞周期蛋白依赖性激酶(CDK)9的特异性抑制剂。体外对白血病细胞增殖具有高度抑制作用, 在急性髓系白血病异种移植模型体内显著抑制肿瘤细胞生长, 并能显著延长小鼠寿命。Molm-13异种移植模型单次灌胃给予QHRD107后, QHRD107迅速被吸收并靶向性分布至肿瘤组织, 肿瘤半衰期(T_1/2)较血浆延长3倍。伴随着肿瘤组织中高浓度QHRD107的暴露, 抗凋亡蛋白Mcl-1 mRNA快速下调, Ki-67细胞表达降低证明肿瘤细胞凋亡。研究结果表明治疗剂量下的QHRD107对AML细胞具有显著的抗肿瘤活性。

关键词: QHRD107, CDK9抑制剂, 疗效, 药代动力学

Abstract:

QHRD107 is a specific inhibitor of cyclin-dependent kinase 9 (CDK9). It is a highly potent antiproliferative agent against leukemia cells in vitro. Oral administration of QHRD107 to mice bearing acute myeloid leukemia tumors markedly inhibited tumor growth. In Molm-13 orthotopic model, QHRD107 resulted in remarkable prolongation of animal life span. After single oral administration of QHRD107 to Molm-13 xenograft model, QHRD107 was quickly absorbed and distributed to tumor with high concentration within 1 h. Tumor half-life time (T_1/2) was three times longer compared with that of plasma. Under the high exposure of QHRD107 in tumor tissue, fast down-regulation of anti-apoptotic protein Mcl-1 mRNA was noted. Reduction of Ki-67 staining in tumor tissue further demonstrated the apoptosis of tumor cells. Therefore, the results provided evidence that QHRD107 at therapeutic dose had significant antitumor activity against AML cell lines.

Key words: QHRD107, CDK9 inhibitor, Efficacy, Pharmacokinetics

Supporting:

周艳, 宋恒文, 邵志超, 尹博民, 付西美, 谢典佑, 韦利军. 一种新的细胞周期蛋白依赖性激酶(CDK)9抑制剂QHRD107对急性髓系白血病的临床前疗效[J]. 中国药学(英文版), 2021, 30(2): 146-156.

Yan Zhou, Hengwen Song, Zhichao Shao, Bomin Yin, Ximei Fu, Dianyou Xie, Lijun Wei. Preclinical efficacy of a novel cyclin-dependent kinase 9 inhibitor, QHRD107 against acute myeloid leukemia[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(2): 146-156.

图/表 8

Table 1. Anti-proliferative effect of QHRD107 against leukemia cell lines.

Figure 1. In vivo antitumor efficacy of QHRD107 in three xenograft models and one orthotopic model. (A) Tumor volume at different days in Molm-13 tumor bearing mice receiving specific treatment (n = 10). (B) Tumor volume at different days in HL-60 tumor bearing mice receiving specific treatment (n = 10). (C) Tumor volume at different days in MV-4-11 tumor bearing mice receiving specific treatment (n = 10). (D) Kaplan-Meier survival plot of Molm-13 orthotopic model treated with vehicle, Ara-C and QHRD107. Data in A to C are shown starting from the first day of dosing and were presented as mean ± SEM. Statistical analysis was done as described in Materials and Methods. P values are relative to the appropriate vehicle control in each case.

Table 2. In vivo antitumor activity for QHRD107 against three leukemia tumor subcutaneous xenografts.

Table 3. The ability of increasing in life span (ILS) for QHRD107 against Molm-13 leukemia orthotopic model (n = 10).

Figure 2. Down-regulation of apoptosis-related biomarker was co-related with QHRD107 exposure in tumor. (A) Pharmacokinetic characterization of plasma and tumor concentration and its relationship with Mcl-1 mRNA expression after oral administration of QHRD107 at 50 mg/kg in tumor bearing mice (n = 3). (B) LC-MS/MS chromatogram of QHRD107 (named as LS007 during discovery stage) with Tolbutamide as IS (upper) 1 h plasma sample after administration, (lower) 1 h tumor sample after administration. Data were presented as mean ± SD. Statistical analysis was done as described in Materials and methods. *Denoted P < 0.05.

Figure 3. IHC staining analysis showing suppression of Ki-67 in tumor bearing mice after treatment of QHRD107. (A) IHC staining analysis of Ki-67 expression in tumor bearing mice (n = 3). (B) Statistical bar graph based on Ki-67 score (percentage of Ki-67 positive cells). NOD/SCID mice were implanted with Molm-13 tumor cells and received a single oral dose of QHRD107 at 50 mg/kg. Tumor tissues were harvested at the designated times after dosing as described in Materials and methods. Tumor tissues from this study incubated with rabbit IgG isotype control were used as negative control. Tumor tissues from HCI-H69 xenograft model incubated with rabbit anti-human Ki67 antibody were used as positive control. Statistical significance of differences in percentage of Ki-67 positive cells between pre-dosing and different time points after treatment were determined by one-way ANOVA. *Denoted P < 0.05.

Table 4. Pharmacokinetic parameters for QHRD107 in Molm-13 tumor bearing mice following single oral administration (n = 3).

Table 5. QHRD107 concentration in tumor at different time point.

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一种新的细胞周期蛋白依赖性激酶(CDK)9抑制剂QHRD107对急性髓系白血病的临床前疗效

Preclinical efficacy of a novel cyclin-dependent kinase 9 inhibitor, QHRD107 against acute myeloid leukemia

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