Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Clinical Problem
1.2. Jak1/2-Stat Pathway
1.2.1. Jak2-Stat5 Signaling Pathway
1.2.2. Jak1-Stat3 Signaling Pathway
1.2.3. Transcription Factor Stat5 Induction of Prostate Cancer Growth, Metastatic Progression and Anti-Androgen Resistance
1.2.4. Transcription Factor Stat3 and Prostate Cancer Growth
2. Development of Pharmacological Jak2 Inhibitors: Type I and II Inhibitors
The First-Generation Jak1/2 Inhibitor Ruxolitinib (INCB018424/Jakafi; Incyte, Novartis)
3. Next-Generation Type I Jak2-Inhibitors with FDA-Approval or in Clinical Development
3.1. Fedratinib (TG101348/SAR302503/Inrebic; TargeGen, Celgene, Bristol Myers Squibb)
3.2. Pacritinib (SB1518/S-BIO; CTI-BioPharma)
3.3. Baricitinib (LY3009104/INCB028050/Olumiant; Eli Lilly)
3.4. Momelotinib (CYT 387; Gilead)
3.5. Gandotinib (LY2784544; Eli Lilly)
3.6. Peficitinib (ASP015K/Smyraf; Astellas)
3.7. Lestaurtinib (CEP-701; Cephalon, Teva Pharmaceuticals)
3.8. Tofacitinib (CP-690550/Tasocitinib/Xeljanz; Pfizer)
3.9. WP1066/WP 1220 (Moleculin Biotech)
3.10. Atiprimod (SKF 106615; AnorMed Inc.)
3.11. Ilginatib (NS-018; NS Pharma)
3.12. AC430/AC410 (Ambit Biosciences)
3.13. LS104 (AEG 41174; Aegara Bio-Therapeutics)
3.14. Jaktinib (Suzhou Zelgen Biopharmaceuticals)
3.15. AT9283 (Astex Pharmaceuticals)
3.16. Cerdulatinib (PRT062070; Portola Pharmaceuticals)
3.17. Filgotinib (GLPG0634/GS-6034/Jyseleca; Galapagos NV)
3.18. Decernotinib (VX 509; Vertex Pharmaceuticals)
3.19. Erlotinib (Tarceva; Genentech)
3.20. Givinostat (ITF2357; ItalFarmaco)
3.21. Repotrectinib (TPX0005; Turning Point Therapeutics)
3.22. Zotiraciclib (TG02; Adastra Pharmaceuticals)
4. Next-Generation Type I Jak2-Inhibitors Currently in Pre-Clinical Development
4.1. NVP-BSK805 (Novartis)
4.2. CEP-33779 (Cephalon Inc./Teva Pharmaceuticals)
4.3. TG101209 (TargeGen/Sanofi)
4.4. AZ960 (AstraZeneca)
4.5. CHZ868 (Novartis)
4.6. ON044580 (Onconova Therapeutics)
4.7. ZT55 (Molnova)
5. Next-Generation Type I Jak2-Inhibitors with the Clinical Development Terminated
5.1. AZD1480 (AstraZeneca)
5.2. XL019 (Exelixis Inc.)
5.3. BMS-911543 (Bristol-Myers Squibb)
5.4. Tozasertib (MK-0457/VX680; Vertex Pharmaceuticals/Merck)
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Drug Name | Mechanism | Indication | NCT # | Trial Phase | Outcome |
---|---|---|---|---|---|
Ruxolitinib * (FDA approved) | Jak1 > Jak2 > Tyk2 > Jak3 inhibitor (Type 1) [105] | Prostate cancer | NCT 03274778 | N/A | Withdrawn: Recruitment difficulty |
Refractory malignant solid neoplasm | NCT 03878524 | 1 | Recruiting | ||
Androgen-independent prostate cancer | NCT 00638378 | 2 | Terminated: Low efficacy | ||
Prostate cancer | NCT 03274778 | N/A | Withdrawn: Recruitment difficulty | ||
Solid tumors (including prostate) | NCT 02711137 | 1/2 | Terminated | ||
Fedratinib * (FDA approved) | Jak2 inhibitor (Type 1) [106] | Solid tumors | NCT 01836705 | 1 | Completed |
Solid tumors | NCT 01585623 | 1 | Completed | ||
Pacritinib * | Jak2 (Type 1) [107] | MF, PCV, post-essential thrombocythemia MF | NCT 02055781 | 3 | Terminated (FDA concerns) |
MF, PCV, post-essential thrombocythemia MF | NCT 03165734 | 3 | Recruiting | ||
COVID | NCT 04404361 | 3 | Recruiting | ||
MF, PCV, post-essential thrombocythemia MF | NCT 02055781 | 3 | Terminated (FDA concerns) | ||
MF, PCV, post-essential thrombocythemia MF | NCT 01773187 | 3 | Terminated (FDA concerns) | ||
NSCLC | NCT 02342353 | 1 | Terminated (drug shortage) | ||
Refractory colorectal cancer | NCT 02277093 | 2 | Terminated (increased side effects) | ||
Baricitinib (FDA approved) | Jak1, Jak2 inhibitor (Type 1) | RA | NCT 01711359 | 3 | Completed |
RA | NCT 01721057 | 3 | Completed | ||
COVID-19 | NCT 04358614 | 2/3 | Completed | ||
RA | NCT 01710358 | 3 | Completed | ||
Momelotinib * | Jak1, Jak2 inhibitor (Type 1) [108] | Symptomatic anemic MF | NCT 04173494 | 3 | Recruiting |
Thrombocytopenia and MF | NCT 02101268 | 3 | Completed | ||
MF | NCT 01969838 | 3 | Completed | ||
Untreated metastatic pancreatic ductal adenocarcinoma | NCT 02101021 | 3 | Terminated (sponsor withdrew) | ||
Adjuvant capecitabine and oxaliplatin in pancreatic ductal adenocarcinoma | NCT 02244489 | 1 | Terminated | ||
NSCLC | NCT 02206763 | 1 | Terminated | ||
Safety/Efficacy in PCV | NCT 01998828 | 2 | Terminated | ||
NSCLC | NCT 02258607 | 1 | Terminated | ||
Gandotinib | Jak2 inhibitor (Type 1) | MF, PCV, ET | NCT 01594723 | 2 | Active |
MF, PCV, ET | NCT 01520220 | 1 | Completed | ||
Healthy males | NCT 01577355 | 1 | Completed | ||
MF, PCV, ET | NCT 01134120 | 1 | Completed | ||
Peficitinib (FDA approved) | Pan-Jak inhibitor (Type 1) | RA | NCT 01638013 | 3 | Completed |
RA | NCT 02308163 | 3 | Completed | ||
RA | NCT 02305849 | 3 | Completed | ||
Lestaurtinib * | FTL3 inhibitor (Jak2 off target inhibitor) | Acute lymphoblastic leukemia | NCT 00557193 | 3 | Active, not yet recruiting |
Asymptomatic hormone-refractory prostate cancer | NCT 00081601 | 2 | Completed | ||
Acute lymphoblastic leukemia | NCT 00557193 | 3 | Active, not yet recruiting | ||
High risk neuroblastoma | NCT 00084422 | 1 | Completed | ||
Tofacitinib * (FDA approved) | Jak3 > Jak2 > Jak1 inhibitor (Type 1) [109] | Previously treated pancreatic adenocarcinoma, cholangiocarcinoma and other mesothelin expressing solid tumors | NCT 04034238 | 1 | Recruiting |
Jak3 > Jak2 > Jak1 inhibitor (Type 1) [109] | Relapsed and refractory extranodal NK/T-cell lymphoma | NCT 03598959 | 2 | Not yet recruiting | |
WP 1066 * | Jak2 inhibitor | Recurrent/progressive pediatric brain tumor | NCT 04334863 | 1 | Recruiting |
Recurrent malignant glioma or Progressive metastatic brain melanoma (18+) | NCT 01904123 | 1 | Recruiting | ||
Atiprimod * | Jak2, Jak3 inhibitor | Neuroendocrine carcinoma | NCT 00388063 | 2 | Completed |
Neuroendocrine carcinoma | NCT 00663429 | 2 | Completed | ||
Multiple myeloma | NCT 00086216 | 1/2 | Completed | ||
Advanced cancer | NCT 00430014 | 1 | Terminated: Sponsor withdrew | ||
Advanced cancer | NCT 00214838 | 1/2 | Unknown, not recruiting. | ||
Ilginatib (NS-018) | Jak2 inhibitor (Type 1) | MF, PCV and post-ET MF | NCT 01423851 | 1/2 | Active |
AC430 | Jak2 inhibitor | Safety in healthy subjects | NCT 01287858 | 1 | Completed |
LS104 | Jak2 inhibitor (allosteric) | Hematological malignancies | Unavailable | 1 | Unknown |
Hematological malignancies | Unavailable | 1 | Unknown | ||
Jaktinib | Jak2 inhibitor | Safety trial in healthy volunteers | NCT 03314402 | 1 | Completed |
MF post Ruxolitinib Intolerance | NCT 04217993 | 2 | Recruiting | ||
Intermediate and high-risk MF | NCT 03886415 | 2 | Recruiting | ||
AT9283 * | Aurora kinase inhibitor (Jak2 off target) | Non-Hodgkin’s lymphoma and solid tumors | NCT 00443976 | 1 | Completed |
Relapsed or refractory multiple myeloma | NCT 01145989 | 2 | Completed | ||
Relapsed or refractory acute leukemia | NCT 01431664 | 1 | Completed | ||
Relapsed or refractory solid tumors in pediatric patients | NCT 00985868 | 1 | Completed | ||
Leukemia dose escalation | NCT 00522990 | 1/2 | Terminated (phase II dose determined) | ||
Cerdulatinib * | SYK and JAK inhibitor | Vitiligo | NCT 04103060 | 2 | Recruiting |
Chronic lymphocytic leukemia, Non-Hodgkin lymphoma | NCT 01994382 | 1/2 | Recruiting | ||
Peripheral T-cell lymphoma | NCT 04021082 | 2/3 | Withdrawn by sponsor, not initiated | ||
Filgotinib (FDA approved) | Jak1 inhibitor (Type 1) | Ulcerative colitis | NCT 02914522 | 3 | Completed |
RA | NCT 02873936 | 3 | Completed | ||
RA | NCT 02886728 | 3 | Completed | ||
RA | NCT 02889796 | 3 | Completed | ||
Testicular safety | NCT 03201445 | 2 | Recruiting | ||
Decernotinib | Jak3 inhibitor (Type 1) | RA | NCT 01830985 | 2/3 | Completed |
Jak3 inhibitor (Type 1) | Healthy subjects | NCT 01886209 | 1 | Completed | |
RA | NCT 01886209 | 2 | Completed | ||
RA | NCT 01590459 | 2 | Completed | ||
Healthy subjects | NCT 00789126 | 1 | Completed | ||
RA | NCT 01052194 | 2 | Completed | ||
Erlotinib * | EGFR inhibitor (Jak2 off target inhibitor) | Chemo-naive, androgen independent prostate cancer | NCT 00272038 | 2 | Completed |
Adjuvant bevacizumab in prostate cancer | NCT 00203424 | 2 | Completed | ||
Non-metastatic prostate cancer with rising PSA | NCT 00148772 | 2 | Completed | ||
Adjuvant docetaxel in older patients with prostate cancer | NCT 00087035 | 2 | Completed | ||
Solid tumors and liver/kidney dysfunction | NCT 00030498 | 1 | Completed | ||
Dose escalation study | NCT 00739453 | 1b | Completed | ||
Drug combination study in various cancers | NCT 03878524 | 1 | |||
Adjuvant bevacizumab in hormone refractory prostate cancer | NCT00996502 | 1/2 | Terminated | ||
Givinostat * | HDAC inhibitor | R/R Hodgkin’s lymphoma | NCT 00792467 | 1/2 | Completed |
Jak2 V617F positive chronic myeloproliferative diseases | NCT 00606307 | 2 | Completed | ||
Chronic myeloproliferative neoplasms | NCT 01761968 | 2 | Active | ||
R/R Hodgkin’s lymphoma | NCT 00496431 | 1/2 | Terminated: Well-tolerated with low efficacy | ||
Repotrectinib * | ROS1 inhibitor with Jak2 (off target) | Solid tumors | NCT 03093116 | 1/2 | Recruiting |
Zotiraciclib * | CDK and Jak1,2 inhibitor | Adults with recurrent anaplastic astrocytoma and glioblastoma | NCT 02942264 | 1/2 | Recruiting |
Drug Name | Mechanism | Indication | NCT # | Trial Phase | Outcome |
---|---|---|---|---|---|
NVP-BSK805 | Jak2 inhibitor (Type 1) | 0 | |||
CEP-33779 | Jak2 > Jak3 inhibitor (Type 1) | 0 | |||
TG101209 | Jak2 inhibitor (type I) | 0 | |||
AZ960 | Jak2 inhibitor (Type 1) | 0 | |||
CHZ868 | Jak2 inhibitor (Type 2) | 0 | |||
ON044580 | Jak2/BCR-ABL dual inhibitor (allosteric) | 0 | |||
ZT55 | Jak2 inhibitor | 0 |
Drug Name | Mechanism | Indication | NCT # | Trial Phase | Outcome |
---|---|---|---|---|---|
AZD1480 | Jak1/2 inhibitor (Type I) [110] | Primary myelofibrosis and post-PCV/ET-MF | NCT 00910728 | 1 | Terminated (toxicity) |
Solid tumors, gastric cancer, HCC, NSCLC | NCT 01219543 | 1 | Terminated (toxicity) | ||
Solid tumors | NCT 01112397 | 1 | Terminated (toxicity) | ||
XL019 | Jak2 inhibitor (Type 1) | PCV | NCT 00595829 | 1 | Terminated (toxicity) |
MF | NCT 00522574 | 1 | Terminated (toxicity) | ||
BMS-911543 | Jak2 inhibitor | MF | NCT 01236352 | 1/2 | Terminated (business decision) |
MK-0457/VX680 | Aurora kinase inhibitor | NCT 00111683 | 1 | Terminated (toxicity) | |
NCT 02532868 | 1 | Terminated (toxicity) | |||
NCT 00290550 | 2a | Terminated (toxicity) | |||
NCT 00405054 | 2 | Terminated (toxicity) | |||
NCT 00099346 | 1 | Terminated (toxicity) | |||
NCT 00500006 | 1 | Terminated (toxicity) |
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Beinhoff, P.; Sabharwal, L.; Udhane, V.; Maranto, C.; LaViolette, P.S.; Jacobsohn, K.M.; Tsai, S.; Iczkowski, K.A.; Wang, L.; Hall, W.A.; et al. Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development? Cancers 2021, 13, 5204. https://doi.org/10.3390/cancers13205204
Beinhoff P, Sabharwal L, Udhane V, Maranto C, LaViolette PS, Jacobsohn KM, Tsai S, Iczkowski KA, Wang L, Hall WA, et al. Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development? Cancers. 2021; 13(20):5204. https://doi.org/10.3390/cancers13205204
Chicago/Turabian StyleBeinhoff, Paul, Lavannya Sabharwal, Vindhya Udhane, Cristina Maranto, Peter S. LaViolette, Kenneth M. Jacobsohn, Susan Tsai, Kenneth A. Iczkowski, Liang Wang, William A. Hall, and et al. 2021. "Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?" Cancers 13, no. 20: 5204. https://doi.org/10.3390/cancers13205204