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

doi:10.5246/jcps.2021.02.012

Abstract

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:

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.

Figures/Tables 8

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

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).

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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