Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis
Abstract
:1. Introduction
2. History of CML Biology and Research
3. Normal Function of Abl1 Tyrosine Kinases
4. Pathogenic Function of Bcr-Abl1 Kinase Fusion Proteins
5. Mutations in Bcr-Abl1 Fusion Protein Have Led to the Development of Several TKIs
6. The Use of TKIs in CML and Their Association with Cardiovascular Disease
7. Mechanism(s) of Ponatinib−Induced Thrombosis
8. Summary and Perspective
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CML | Chronic Myeloid Leukemia |
ALL | Acute Lymphoblastic Leukemia |
TKI | Tyrosine Kinase Inhibitors |
Bcr−Abl1 | Breakpoint Cluster Region Protein−Abelson Tyrosine−Protein Kinase 1 |
EPIC | Evaluation of Ponatinib Versus Imatinib in Chronic Myeloid Leukemia |
PACE | PIVOTAL Phase−II Ponatinib Ph+ ALL and CML Evaluation |
ENESTn | Randomized Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients |
PT | Prothrombin Time |
aPTT | Activated Partial Thromboplastin Time |
TGT | Thrombin Generation Times |
ROS | Reactive Oxygen Species |
CRP | Collagen−Related Peptide |
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Imatinib | Nilotinib | Bosutinib | Dasatinib | Ponatinib | |
---|---|---|---|---|---|
ABL1 | 83 | 98 | 100 | 105 | 101 |
ABL2 | 68 | 95 | 99 | 102 | 100 |
AKT1 | 3 | 11 | −5 | 3 | 9 |
AKT2 | 4 | 12 | −3 | 6 | 7 |
AKT3 | 4 | 2 | 1 | 5 | 16 |
BLK | 23 | 29 | 84 | 103 | 97 |
BTK | −1 | 45 | 97 | 102 | 95 |
CDK4/CycD3 | 3 | −4 | −7 | 3 | 24 |
CHK1 | 10 | −15 | 83 | 11 | 3 |
CHK2 | 6 | −12 | 87 | 4 | 96 |
CSK | −2 | 78 | 84 | 104 | 102 |
EEF2K | −2 | 6 | −7 | 3 | −4 |
EGFR | 4 | 17 | 100 | 102 | 97 |
EPHA1 | 9 | 61 | 3 | 101 | 97 |
EPHA4 | 5 | 91 | 86 | 99 | 101 |
EPHB1 | 7 | 72 | 98 | 100 | 100 |
Erk1 | −5 | 3 | 1 | −5 | −2 |
Erk2 | −8 | 1 | −4 | −7 | −7 |
Erk5 | 17 | −4 | 3 | 5 | 3 |
FAK | 29 | 3 | 22 | 17 | −23 |
FGFR1 | −1 | −29 | 79 | 47 | 101 |
FGFR2 | 3 | −67 | 95 | 73 | 100 |
FGFR3 | 1 | −11 | 83 | 34 | 101 |
FGFR4 | 8 | −7 | 3 | 9 | 98 |
FGR | 28 | 55 | 92 | 103 | 101 |
VEGFR1 | 5 | 32 | 97 | 39 | 101 |
VEGFR2 | 7 | 22 | 101 | 22 | 94 |
VEGFR3 | 3 | 17 | 92 | 31 | 101 |
FLT3 | 68 | 60 | 77 | 17 | 99 |
FRK | 9 | 70 | 94 | 100 | 100 |
FYN | 30 | 59 | 95 | 100 | 101 |
HCK | 13 | 73 | 89 | 100 | 98 |
JAK1 | −1 | 13 | −2 | 9 | 99 |
JAK2 | 0 | 19 | 64 | 68 | 92 |
KIT | 97 | 96 | 23 | 100 | 101 |
LCK | 80 | 90 | 101 | 102 | 103 |
LYN | 76 | 85 | 93 | 100 | 100 |
PDGFRα | 98 | 103 | 77 | 100 | 103 |
PDGFRβ | 91 | 93 | 95 | 99 | 102 |
SRC | 5 | 23 | 96 | 101 | 102 |
SYK | 16 | 54 | 100 | 69 | 10 |
TIE2 | 0 | 41 | 22 | 16 | 101 |
YES | 22 | 44 | 97 | 102 | 101 |
ZAP70 | 10 | 3 | 76 | 12 | 5 |
TKIs | Imatinib | Nilotinib | Bosutinib | Dasatinib | Ponatinib | Asciminib |
---|---|---|---|---|---|---|
Binding conformation | closed | closed | Both | Open | Closed | Myristoyl pocket |
Resistance | T315 Y253 E255 M244 L248 G250 Q252 F317 M351 M355 F359 H396 | T315 L248 Y253 E255 F359 | T315 V299 L248 G250 E255 F317 | T315 V299 F317 | E255 | A337 W464 P465 V468 I502 |
TKIs/Syndromes | Imatinib | Nilotinib | Bosutinib | Dasatinib | Ponatinib | Asciminib |
---|---|---|---|---|---|---|
Cardiac arrhythmias | 0.3(0.1–1.4) | 2.7(2.1–3.5) | 1.6(0.2–11.7) | 1(0.6–1.6) | 1(0.5–2.2) | NA |
Cardiac failure | 1.1(0.8–1.6) | 1.5(1.3–1.7) | 3.5 (1.9–6.6) | 4.1(3.7–4.6) | 1.8(1.4–2.4) | NA |
Cardiomyopathy | 1.2(0.7–2.0) | 0.4(0.2–0.6) | NA | 0.4(0.3–0.7) | 0.6(0.3–1.2) | NA |
Embolic, thrombotic | 0.4(0.3–0.5) | 1.3(1.1–1.4) | 1(0.5–1.9) | 0.5(0.4–0.6) | 1.4(1.2–1.6) | NA |
Hypertension | 0.2(0.1–0.5) | 0.9(0.8–1.1) | 1.2(0.4–3.7) | 0.8(0.6–1.0) | 3.5(2.9–4.3) | NA |
Ischemic heart | 0.6(0.4–0.9) | 6.7(6.2–7.2) | 2.5(1.3–4.8) | 1.0(0.8–1.2) | 2.9(2.4–3.5) | NA |
Pulmonary hypertension | 3.9(2.4–6.4) | 1.1(0.6–1.7) | NA | 8.5(6.8–10.6) | 1.3(0.6–3.9) | NA |
QT prolongation | 0.8(0.6–2.5) | 12.2(10.3–14.6) | NA | 2.5(1.6–3.7) | 0.9(0.3–2.4) | NA |
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Zeng, P.; Schmaier, A. Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis. Int. J. Mol. Sci. 2020, 21, 6556. https://doi.org/10.3390/ijms21186556
Zeng P, Schmaier A. Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis. International Journal of Molecular Sciences. 2020; 21(18):6556. https://doi.org/10.3390/ijms21186556
Chicago/Turabian StyleZeng, Peng, and Alvin Schmaier. 2020. "Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis" International Journal of Molecular Sciences 21, no. 18: 6556. https://doi.org/10.3390/ijms21186556