Medicinal Chemistry Progression of Sapanisertib, the Anticancer and Dual Plasmodium Phosphatidylinositol 4‑Kinase Beta and cGMP-Dependent Protein Kinase Inhibitor, for Malaria

TL;DR

This paper explores the development of sapanisertib, an anticancer drug, as a potential treatment for malaria by inhibiting key Plasmodium enzymes.

Contribution

The study identifies new sapanisertib analogs with improved safety and antimalarial activity, including dual inhibitors of Plasmodium PI4Kβ and PKG.

Findings

Compound 19 shows potent antimalarial activity and high metabolic stability with a favorable safety profile.

Compound 20 is a potent Plasmodium PI4Kβ inhibitor with minimal PKG inhibition.

Oral administration of compound 19 reduced parasitemia by 80% in infected mice.

Abstract

We recently demonstrated that the anticancer human mTOR
inhibitor
sapanisertib displays antimalarial activity in a malaria mouse model
of infection and inhibits multiple Plasmodium kinases,
including the high-value targets phosphatidylinositol 4-kinase type
III beta (PI4Kβ) and cGMP-dependent protein kinase (PKG). Herein,
we explore structure–activity relationships for sapanisertib
analogues with benzyl and pyridyl substituents at the 7-position of
the pyrazolopyrimidine core. New analogues with improved safety profiles
were identified, including analogues with dual Plasmodium PI4Kβ and PKG inhibitory activity (exemplified by 19), as well as potent Plasmodium PI4Kβ inhibitors
with minimal inhibitory activity against PKG (exemplified by 20). Compound 19 displayed potent antiplasmodium
activity, high microsomal metabolic stability, and a good safety profile
(hERG IC50 > 30; cytotoxicity selectivity index = 99).
In vivo proof-of-concept, where a 4 × 50 mg kg–1 oral dose of 19 resulted in an 80% reduction in parasitemia
in P. berghei-infected mice, further
demonstrated the lead potential of this series.

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