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22nd January 2015 @ 23:47

Melanie Ridgeway in Kiaran Kirk’s laboratory completed some cross-resistance studies, looking at growth-inhibition by several of the OSM Series 4 compounds of several Kirk ATP4 mutant strains (generated by long-term exposure to increasing concentrations of three Malaria Box hits, as documented in their recent paper).

The data are attached to this post. Each graph is averaged from three independent experiments. Upshot: Data are supportive of Series 4 targeting ATP4.

Series 4 growth assays[1].pdf

Each of the six panels shows the response of four strains (the Dd2 parent and three different PfATP4 mutants) to a different compound.  Panels A-C show growth inhibition by three different Series 4 compounds. Panel D shows growth inhibition by NITD/KAE 609. Panels E and F show growth inhibition by chloroquine and artemisinin.

The three mutant PfATP4 strains show resistance to all three of the Series 4 compounds (Panels A-C) and to NITD609 (Panel D), providing further evidence of a common mechanism of action.

(Note: For two of the three mutant strains there is no significant shift of the chloroquine or artemisinin dose-response curves. But for one of the three mutants there is what appears to be small shifts in the artemisinin and chloroquine dose-response curves, with the artemisinin and chloroquine curves shifted in opposite directions.  The meaning of this is currently unclear.)

Attribution for these data: Kiaran Kirk, Adele Lehane, Melanie Ridgeway. Received by email to Mat Todd, 20th October 2014.

Compound Structures:

Compounds used to generate ATP4 mutants

Compound Strings:

NITD609 KAE609 C[C@@H](C1)N[C@@]2(C(NC3=C2C=C(Cl)C=C3)=O)C4=C1C5=CC(F)=C(Cl)C=C5N4 InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1 CKLPLPZSUQEDRT-WPCRTTGESA-N

MMV011567 O=C(C1=CC(Cl)=C(OC)C=C1)NC2=NON=C2C3=CC=C(OC)C(OC)=C3 InChI=1S/C18H16ClN3O5/c1-24-13-6-5-11(8-12(13)19)18(23)20-17-16(21-27-22-17)10-4-7-14(25-2)15(9-10)26-3/h4-9H,1-3H3,(H,20,22,23) RUPCNQRICRCGRU-UHFFFAOYSA-N

MMV007275 ClC(C=C1C(NC2=C(C)C=CC(F)=C2)=O)=CC=C1NC3=CC=CC=C3 InChI=1S/C20H16ClFN2O/c1-13-7-9-15(22)12-19(13)24-20(25)17-11-14(21)8-10-18(17)23-16-5-3-2-4-6-16/h2-12,23H,1H3,(H,24,25) YDYIMBIBJGKUCE-UHFFFAOYSA-N

MMV670944 O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-13(30(15)16)17(31)27-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,(H,26,27,31) UEOZBGRWGZEYED-UHFFFAOYSA-N

MMV670767 O=C(NC1=CC=C(F)C(Cl)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C19H11ClF3N5O2/c20-13-7-11(3-6-14(13)21)25-18(29)15-8-24-9-16-26-27-17(28(15)16)10-1-4-12(5-2-10)30-19(22)23/h1-9,19H,(H,25,29) WFJPUMPZNOYIKX-UHFFFAOYSA-N

MMV671677 O=C(NCC1=C(Cl)C(C(F)(F)F)=CC=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H13ClF5N5O2/c22-17-12(2-1-3-14(17)21(25,26)27)8-29-19(33)15-9-28-10-16-30-31-18(32(15)16)11-4-6-13(7-5-11)34-20(23)24/h1-7,9-10,20H,8H2,(H,29,33) YLYCMIJACQNNRW-UHFFFAOYSA-N

Attached Files
Series 4 growth assays[1].pdf
Kiaran Resistance Structures.cdxml
Kiaran Resistance Structures.png