Table 5.
Retrospective Analysis of Sentinel Kinase Model Using Clinically Tested SMKI
| SMKI | Primary Target | Cardiotoxicity | Cmaxss (µM) | IC50 (µM) |
||
|---|---|---|---|---|---|---|
| FAK | RPS6KB1 | STK35 | ||||
| Ibrutinib1,2 | BTK | FDA-approved: no warnings | 0.3 | >3.2 | >3.2 | 1.1 |
| Dabrafenib3,4 | B-Raf | FDA-approved: no warnings | 4.7 | 78.8 | 0.5 | 14.5 |
| Palbociclib5,6 | CDK4/6 | FDA-approved: no warnings | 0.1 | >3.2 | >3.2 | >3.2 |
| Tofacitinib7,8 | JAK1/3 | FDA-approved: no warnings | 0.1 | >3.2 | >3.2 | >3.2 |
| Telatinib9 | VEGFR2/3, c-Kit | DLT (phase I): hypertension | 2.0–3.6 | >32 | >32 | >32 |
| Tivozanib10 | VEGFR1/2/3 | DLT (phase I): hypertension | 0.2 | 3.1 | >3.2 | >3.2 |
| Ponatinib11 | BCR-ABL | FDA approved with black box warning: Arterial Thrombosis. Other hazards: thrombosis, occlusions, fatal myocardial infarction, stroke, stenosis, heart failure, left ventricular dysfunction | 0.1 | 3.1 | 0.2 | 0.1 |
| Regorafenib12 | VEGFR2, TIE2 | FDA approved with warnings and precautions: hypertension and cardiac ischemia and infarction | 8.1 | >100 | 10.9 | 7.5 |
| Vemurafenib13 | B-Raf | FDA approved with warnings and precautions: prolonged QT. Atrial fibrillation also listed as a clinically relevant adverse event. | 126.6 | >100 | >100 | 39.7 |
| Cabozantinib 14,15 | c-Met VEGFR2 | FDA approved with warnings and precautions: hypertension and thrombotic events | 2.8 | 2.8 | 13.2 | 5.7 |
| Ceritinib16,17 | ALK | FDA approved with warnings and precautions: bradycardia and QT interval prolongation | 1.4 | <0.1 | >32 | 5.9 |
| Lenvatinib18,19 | VEGFR1/2/3 FGFR1/2/3/4 PDGFRα c-Kit, RET | FDA approved with warnings and precautions: hypertension, cardiac dysfunction, thrombolytic events, QT interval prolongation | 1.4 | 65.2 | 25.4 | 1.3 |
| Sotrastaurin20,21 | PKC | Significant finding (phase II trial): tachycardia | 1.4* | 7.3 | 0.3 | >32 |
| PF-381473522 | Aurora A/B | DLTs (Phase I): left ventricular dysfunction | 4.4 | <0.3 | <0.3 | 0.4 |
| AT-928323 | Aurora A/B, Jak2/3, c-ABL | DLTs (phase I): myocardial infarction, hypertension, and cardiomyopathy | 0.05–3.3 | 0.8 | 0.03 | 0.6 |
| ENMD-207624 | Aurora A, Flt3 | DLTs (phase I): hypertension and congestive heart failure | 0.6–1.5 | 10.9 | 0.6 | >10 |
| AZD776225 | Chk1/2 | DLTs (phase I): elevated troponin, myocardial ischemia, and myocardial infarction with ventricular dysfunction | 0.1–1.1 | 0.1 | 3.0 | >3.2 |
| SCH90077626 | Chk1 | DLTs (phase I): QT interval prolongation (alone), and supraventrical tachycardia and atrial fibrillation (in combination with gemcitabine) | 3.2–15.2 | >30 | 1.0 | 30.0 |
| Trametinib27,28 | FDA approved with warnings and precautions: cardiomyopathy. Hypertension also listed as a clinically relevant adverse event. | 0.04 | >1 | >1 | >1 | |
Comparison of clinical cardiac liabilities, human plasma exposure [steady state Cmax (Cmaxss)], and binding profile to FAK, RPS6KB1, and STK35 for clinically tested SMKI. Cardiac liability data were derived from FDA inserts and Pharmaprojects, January 2015 (Pharma Intelligence) and Trialtrove, January 2015 (Pharma Intelligence). “Cardiac safe” SMKI are highlighted in white, VEGF inhibitors with hypertension DLT are highlighted in light grey, and “cardiotoxic” SMKI and their associated cardiotoxicities are highlighted in dark grey. Cmax at steady state (Cmaxss) or Cmax after a single dose (indicated by *) are displayed for each SMKI. The kinase binding IC50 is highlighted in dark grey if the IC50 ≤ Cmaxss. IC50 values are listed as “>X” for compounds showing <50% inhibition at the highest concentration tested (specified as X µM). References denoted by superscript numbers are included in Supplementary Text.