Recent Progress of Oridonin and Its Derivatives for the Treatment of Acute Myelogenous Leukemia

Abstract

First stage human clinical trial (CTR20150246) for HAO472, the L-alanine-(14-oridonin) ester trifluoroacetate, was conducted by a Chinese company, Hengrui Medicine Co. Ltd, to develop a new treatment for acute myelogenous leukemia. Two patents, WO2015180549A1 and CN201410047904.X, covered the development of the I-type crystal, stability experiment, conversion rate research, bioavailability experiment, safety assessment, and solubility study. HAO472 hewed out new avenues to explore the therapeutic properties of oridonin derivatives and develop promising treatment of cancer originated from naturally derived drug candidates. Herein, we sought to overview recent progress of the synthetic, physiological, and pharmacological investigations of oridonin and its derivatives, aiming to disclose the therapeutic potentials and broaden the platform for the discovery of new anticancer drugs.

A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein

“…Moreover, a full Ki/Kinact analysis would ideally delineate between the stages of oridonin's Nsp9-binding, its adduct formation and consequent reduced NiRAN activity. The overall ent-kaurene framework within compound 2 has been assessed in clinical trials (CTR20150246) at intravenous dosages of up to 320 mg/d (40). We observed some cell-line specific cytotoxicity for oridonin and this necessitates a degree of caution when drawing conclusions from cellular viral replication assays.…”

Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis

“…In this study, we screened drug libraries containing a total of 3917 compounds and identified that oridonin inhibits DNMT3A R882 mutant leukemic cells and Dnmt3a R878H HSCs in vitro and in vivo. The broad-spectrum anticancer effects and the underlying mechanisms of oridonin have been studied for decades [ 18 , 37 , 38 ], and the mechanistic studies primarily focused on genes involved in apoptosis-related and autophagy-related signaling pathways [ 39 – 42 ]. In addition to revealing the proapoptotic effect of oridonin, our study provides evidence for the first time that necroptosis participates in the cell death induced by oridonin in hematological malignancies with DNMT3A mutations.…”

“…The data we obtained from the in vitro and in vivo experiments support the hypothesis that oridonin effectively inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia, and this provides the preclinical evidence for the possible clinical investigation of oridonin for DNMT3A-mutant leukemia. Furthermore, a prodrug of oridonin called HAO472 has been enrolled into Phase I human clinical trial (CTR20150246; www.chinadrugtrails.org.cn ) in China for targeting AML1-ETO [ 37 ], which could highly facilitate the translation of our findings into clinical investigations for patients bearing DNMT3A mutations in the near term.…”

Tumor microenvironment‐activatable oridonin‐loaded iron‐based metal–organic frameworks for targeting cancer therapy

“…16 It is mainly used for the treatment of liver cancer, esophageal cancer, pancreatic cancer, and other diseases. [17][18][19][20] However, the shortcomings of short half-life, limited bioavailability, and low water solubility of Ori have limited its clinical application. [21][22][23] Therefore, improving its bioavailability has become an urgent problem to solve.…”