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. 2024 Oct 4;10(40):eado7120. doi: 10.1126/sciadv.ado7120

Fig. 1. BCL-XL–selective inhibitors cause on-target cardiovascular toxicity in dogs.

Fig. 1.

(A) In instrumented, anesthetized beagle dogs’ heart rate and mean arterial blood pressure drop precipitously approximately 60 min following an intravenous bolus dose (2.5 mg/kg) of A-1331852 (left; n = 2). Marked reduction in R-wave amplitude in electrocardiogram tracings at 0 and 60 min after dosing (right). (B) Left: Hematoxylin and eosin–stained heart demonstrates nuclear pyknosis of an endothelial cell (arrow) and a comparatively normal nucleus (arrowhead). Top right: Cardiac endothelial cells are immunoreactive (brown) for activated caspase-3 in an A-1331852 (2.5 mg/kg)–treated dog 90 min after dosing, whereas no activated caspase-3 is detected in a dog treated with structurally related inactive compound 3 (2.5 mg/kg) that does not cause cardiovascular collapse (bottom right). (C) Electron photomicrograph of a myocardial capillary from dog treated intravenously with active compound 2 (left), approximately 90 min after an intravenous dose (2.5 mg/kg). An erythrocyte [red blood cell (RBC)] is present within a well-defined capillary (arrows). Right: The endothelium is collapsed with condensed nuclear material (*) and intracytoplasmic vesicles (arrows) approximately 90 min following an intravenous dose (2.5 mg/kg) of a potent SMI 2. Scale bar, 2 μm (on electron micrograph). (D) Plasma A-1331852 is rapidly cleared following an intravenous dose (2.5 mg/kg), shown as mean from the same two dogs. Platelet count and serum IL-10 rapidly fall from baseline levels following dosing, whereas serum MCP-1 increases and remains elevated from 30 min after dosing. Error bars are SEM. (E and F) Structure, binding affinity, and cellular potency of molecules used in anesthetized dog studies and navitoclax, as well as the plasma concentration (in micrograms per milliliter) of each molecule evaluated in the dog studies at 5 and 90 min after initiation of study. The RS4;11 and Molt-4 cell lines are dependent on BCL-2 and BCL-XL, respectively. NT, not tested.