Abstract
In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds’ mechanisms of action—i.e., the specific molecular targets by which they kill the parasite—would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children’s Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 μM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible.
Highlights
While screens of compound libraries for anti-Plasmodium activity are nothing new [1], there has been a recent trend toward public disclosure of all hit compounds arising from these screens [2,3,4]
Since the P. falciparum Mitogen-Associated Protein Kinase 2 (MAPK2) may share some features with cyclin-dependent kinases (CDKs), various CDK inhibitors as well as the MAP kinase inhibitor BIRB796 were tested for possible use as a control inhibitor
We attained mixed results in our effort to link anti-Plasmodium compounds with possible P. falciparum protein kinase targets
Summary
While screens of compound libraries for anti-Plasmodium activity are nothing new [1], there has been a recent trend toward public disclosure of all hit compounds arising from these screens [2,3,4] These disclosures facilitate follow-up studies of these “cell-active” compounds and accelerate progress toward new antimalarial drugs. Many challenges remain in developing compounds with activity against culture-grown Plasmodium cells into clinically effective drugs [5]. Among these is identifying the compounds’ mechanism of action, i.e., the specific molecular targets by which they kill the parasite. Despite the ubiquity of ATP binding sites, selective and potent inhibition of individual kinases has been achievable for both infectious and non-infectious diseases [6,7]; kinases as a class are considered “druggable.” the Plasmodium kinome includes many potentially exploitable differences with respect to the human kinome [8], and kinome-wide essentiality data [9,10] further enable prioritization of possible Plasmodium kinase targets
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