A Novel 2-Carbon-Linked Dimeric Artemisinin With Potent Antileukemic Activity and Favorable Pharmacology.

Amanda B Kagan,Ganesha Rai,Nicole M Anders,Curt I Civin,Bryan T Mott,Blake S Moses,Michelle A Rudek

doi:10.3389/fonc.2021.790037

Abstract

Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented in vivo antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.

Highlights

The prognosis for patients with acute myeloid leukemia (AML) remains poor (5-year survival ~ 2530%) and is dismal for patients who are over 60 years old, unfit, or with relapsed/ refractory disease, unfavorable cytogenetics, or certain molecular abnormalities [1]
The K562 cell line was the only exception, as it was resistant to all 3 of these ARTs. Based on this in vitro activity data combined with the drug stability data described below, ART631 was prioritized over ART576 for further in vitro and in vivo antileukemic efficacy experiments here (Table 2)
Multiple 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) derivatives had previously demonstrated potent in vivo efficacy in a malaria model [19], suggesting good drug-like pharmacology. Their extended patent protection, physicochemical features, and in vivo antimalarial activity indicated that 2C-ART derivatives might be more attractive for development as antineoplastics, compared to earlier ART derivatives including ART838

Summary

Introduction

The prognosis for patients with acute myeloid leukemia (AML) remains poor (5-year survival ~ 2530%) and is dismal for patients who are over 60 years old, unfit, or with relapsed/ refractory disease, unfavorable cytogenetics, or certain molecular abnormalities [1]. Improved understanding of the pathophysiology and mutational landscape of AML has stimulated the successful development of a number of targeted therapies. Nine new AML therapeutics – including inhibitors of B-cell lymphoma 2 (BCL2), FMS-like tyrosine kinase 3 (FLT3), and isocitrate dehydrogenase (IDH) – were approved by the FDA between 2017 and 2021 [1, 3]. Novel Artemisinin for Leukemia Treatment therapy resistant AML in the majority of patients with targetable mutations [4,5,6]. There has been growing interest in additional new agents and combination regimens with novel mechanisms that may be non-cross resistant with respect to current antileukemic drugs, and that suggest low clinical toxicity

Methods

Results

Conclusion