Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer
Abstract
:1. Introduction
Kinase | Role in CRPC | Inhibitor | Chemical Structure | Mechanism of Inhibition | Reference |
---|---|---|---|---|---|
PLK1 | PLK1 signaling is one of the most up-regulated pathways after androgen deprive in mouse xenograft. PLK1 activation promotes CRPC development through affecting the PI3K–AKT–mTOR pathway and androgen receptor (AR) signaling. | BI2536 (combined with olaparib) | | Since monotherapy with olaparib leads to high expression of PLK1, PLK1 inhibitor can significantly increase the efficacy of olaparib. | [13] |
GSK461364A (combined with BRD4 inhibitor, JQ1) | | Inhibits PLK1, c-MYC expression and AR signaling | [14] | ||
WNY0824 | | Inhibit AR transcriptional program, down-regulate MYC and induce mitotic abnormality | [15] | ||
BRD4/BET | Bind to SEs that drive high expression of oncogenes; BRD4 together with HOXB13 regulated transcriptional networks to support androgen-independent cell proliferation of CRPC | JQ1 (combined with PLK1 inhibitor, GSK461364A) | | Inhibits PLK1, c-MYC expression and AR signaling; down-regulating SE-associated genes, including genes involved in migration and invasion, especially a long non-coding RNA, MANCR | [14,16] |
MA4-022-1 compound | | Interfere BRD4-HOXB13-HOTBIN10 regulatory circuit | [17] | ||
(R)-12 (Y02234) | | Bind to BRD4 and block the interaction between bromodomain and acetyl lysine; suppress ERG, Myc, and AR signaling | [18] | ||
6i (Y06036) and 7m (Y06137) | 6i | Bind to BRD4 and suppress expression of MYC and AR regulated genes | [19] | ||
7m | |||||
ABBV-075 | | Disrupt the recruitment of BRD4 to gene-regulatory regions co-occupied by AR, including PSA and TMPRSS2 enhancers, leading to the inhibition of transcription of AR target genes | [20] | ||
Compound 7d | | Disrupt the functions of AR and BET via binding to AR and suppressing transactivation of AR as well as AR mutant | [21] | ||
LIMK2 | LIMK2 involves in CRPC progression through increasing TWIST1 mRNA levels and stabilizing TWIST1 by phosphorylation, mediating SPOP degradation | LIMK2 allosteric inhibitor (sulfonamide 2) (combined with docetaxel) | | Is non-ATP competitive (allosteric inhibition) and binds in the DFG-out orientation of kinase | [10,22] |
MEK | MEK1/2 promotes CRPC progression via regulating their downstream target such as ERK1 | Selumetinib (AZD6244) (combined with ricolinostat (ACY1215)) | | Decrease AR-dependent gene (KLK2, DUSP1) mRNA levels; increase AR cytoplasmatic expression | [23,24] |
AURKA | AURKA is overexpressed in CRPC, regulates androgen receptor variants (AR-Vs) expression, and acts as a phosphatase and functions through regulating its substrates, including YBX1, TWIST1, and LIMK2. | MLN8237 (alisertib) | | Inhibit the growth of CRPC cells with high levels of AR | [7] |
S1451 (TC-S 7010) | | Decrease AR-V7 levels and markedly reduce AR-V-driven proliferation and survival of CRPC cells | [25] | ||
TOPK | TOPK drives androgen-independent growth in prostate cancer cells (LNCaP and VCaP) via enhancing androgen receptor splice variant (ARv7) | OTS-514 | | Repress AR transactivation, and AR stability | [26] |
GSK-3 | Promote AR-V7 transcription | LY 2090314 | | Activate β-catenin signaling, which suppressed AR-V7 transcriptional activity | [27] |
CDK9 | A cofactor for AR, MYC and other oncogenic transcription factors | KB-0742 | | Down-regulate nascent transcription, especially AR-driven oncogenic programs and short half-life transcripts | [28] |
CDK4 | Regulate cell cycle progression | Pso (3, 9-dihydroxy-2-prenylco- umestan (psoralidin)) | | Induce G0/G1 cell cycle arrest and cell growth inhibition in CRPC cells | [29] |
CDK7 | Regulate MED1-mediated, AR-dependent oncogenic transcriptional amplification | THZ1 | | Interfere the recruitment of MED1 to chromatin and further suppress AR target gene expression | [30,31] |
IκB kinase (IKK) | Phosphorylate IκBα, resulting in the degradation of IκBα and release of p50/p65. The p50/p65 translocates into nucleus to start the transcription of NF-κB-regulating genes | Ursolic acid | | Inhibit IKK activation and phosphorylation of IκBα | [32] |
Apigenin | | Inhibit IKKα kinase activity, and IκBα phosphorylation and degradation | [33] | ||
α-tomatine | | Inhibit IκB kinase-mediated IκBα phosphorylation, IκBα degradation and p50/p65 nuclear translocation | [34] | ||
PKA | PKA activation phosphorylates heat shock protein (HSP90), which binds to the unliganded AR in cytoplasm, and release AR from HSP90. The free AR binds to HSP27 and sequentially migrates into the nucleus | H89 | | Inhibit the PKA activity and AR translocation | [35] |
PIM1 | Modulate AR stability and transcriptional activity through phosphorylating AR | Compound 9 (DHPCC-9) and its pyrrolo[2,3-a]carbazole derivatives | (compound 9 R=H; compound 28 R=Br) | Inhibit the PIM1 kinase activity | [36] |
DHPCC-9 (1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde) | | Inhibit angiogenesis and lymphangiogenesis as well as phosphorylation of the CXCR4 chemokine receptor | [37] | ||
Ack1 | Phosphorylate AR-tyrosine 267 | AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) | | Inhibit Ack1 tyrosine kinase activity and suppress Ack1 mediated ATM | [38] |
JAK2 | Phosphorylate Stat5a/b, regulate its dimerization, nuclear translocation, DNA binding and transcriptional activity | β-elemonic acid (β-EA) | | Suppress of JAK2/STAT3/MCL-1 and NF-ĸB signaling pathway | [39] |
EGFR | Promote CRPC progression through regulating its downstream signaling; mediated docetaxel resistance in human CRPC via Akt-dependent expression of ABCB1 | Gefitinib | | Inhibit EGFR activity | [40] |
HER2 | Form EGFR/HER2 heterodimerization and regulate downstream signaling to promote CRPC | dacomitinib | | Decrease HER2 protein stability and prevent EGFR/HER2 heterodimerization, therefore interrupting downstream signaling and increasing CRPC cell apoptosis | [41] |
RET | Is up-regulated in NEPC, and RET expression correlated with neuroendocrine transcription factors, including POU3F2, SOX2, ONECUT2 and ASCL1 | AD80 | | block RET signaling | [42] |
PIP5K1α | PIP5K1α produces a substrate of PI3K, PIP2, which is required for the activation of PI3K/AKT pathway | ISA-2011B | | Inhibit AKT activity, reduce invasion, increase cancer cell apoptosis and inhibit tumor growth in CRPC model | [43] |
SK1 | High levels of SK1 have been identified, and SK1 level and activity are associated with prostate cancer progression, recurrence and chemoresistance | FTY720 (fingolimod) | | Activate caspase-3 and induce apoptosis | [44,45,46] |
SK2 | Regulate expression of the oncogene c-Myc and promote PCa progression | ABC294640 | | Reduce CRPC cell growth and the expression of c-Myc and AR; inhibit dihydroceramide desaturase (DEGS), resulting in the increase of dihydroceramides | [47] |
HK2 | Increased HK2 expression and activity is associated with CRPC development, especially PTEN- and TP53-deficiency-driven CRPC | 2-deoxyglucose (2-DG) | | Cause AMPK phosphorylation, leading to inhibit mTORC1-S6K1 translation signaling and sequentially block anti-apoptotic protein MCL-l synthesis | [48] |
Inhibitor | Chemical Structure | Target | Clinical Trial Phase | Model System/Patient Characteristics | Treatment | Results | Reference |
---|---|---|---|---|---|---|---|
Alisertib | | AURKA | Phase II (NCT01799278) | Patients with castration-resistant and neuroendocrine prostate cancer | Alisertib | Some but not all patients with NEPC with Aurora-A and N-Myc activation do benefit from alisertib. | [49] |
Alisertib | AURKA | I/II (NCT01848067) | Patients with metastatic castration-resistant prostate cancer | Alisertib in combination with abiraterone and prednisone | No clear signal indicates that alisertib might be beneficial for patients with mCRPC progressing on abiraterone | [50] | |
Alisertib | AURKA | I (NCT01094288) | Patients with solid tumors, including CRPC | Alisertib combines with docetaxel | 1 complete response in a patient with bladder cancer, six partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. | [51] | |
AZD5363 (Capivasertib) | | AKT | I (NCT02121639) | Patients with metastatic castration-resistant prostate cancer | AZD5363 combines with docetaxel and prednisolone chemotherapy | PSA reduction to <50% at 12 weeks occurred in seven patients | [52] |
AZD5363 (Capivasertib) | AKT | I (NCT02525068) | mCRPC patients who previously failed abiraterone and/or enzalutamide | AZD5363 combines with enzalutamide | Decrease plasma exposure of capivasertib; Three patients show the criteria for response | [53] | |
BKM120 (Buparlisib) | | PI3K | II (NCT02035124) | Patients with metastatic castration-resistant prostate cancer | cabazitaxel plus BKM120 | Withdrawn due to slow accrual and no patients being enrolled | https://clinicaltrials.gov/ct2/show/NCT02035124?term=PI3K+inhibitor&cond=CRPC&draw=2&rank=1 (30 October 2021) |
AZD8186 | | PI3Kbeta | I (NCT03218826) | Patients with advanced solid tumors, including advanced prostate carcinoma | AZD8186 plus docetaxel | Expected completion: 1 April 2022. Outcome measure: Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D); incidence of adverse events | https://clinicaltrials.gov/ct2/show/NCT03218826?term=PI3K+inhibitor&cond=CRPC&draw=2&rank=3 (30 October 2021) |
LY3023414 (Samotolisib) | | PI3K/mTOR | II (NCT02407054) | Patients with prostate cancer, including metastatic castration-resistant prostate cancer | Enzalutamide plus LY3023414 | Outcome measure: progression free survival (PFS); time to disease progression (TTP) | https://clinicaltrials.gov/ct2/show/NCT02407054?term=PI3K+inhibitor&cond=CRPC&draw=2&rank=4 (30 October 2021) |
ZEN003694 | This compound is under clinical trial and its structure is unpublished. | BET Bromodomain | II (NCT04471974) | Patients with metastatic castration-resistant prostate cancer | ZEN003694 plus enzalutamide and pembrolizumab | Expected completion: 31 December 2025. Outcome measure: composite response rate; progression-free survival (PFS); PSA50 response proportion | https://clinicaltrials.gov/ct2/show/NCT04471974?term=BET+inhibitor&cond=CRPC&draw=2&rank=1 (30 October 2021) |
ZEN003694 | BET Bromodomain | Ib/IIa (NCT02711956) | Patients with metastatic castration-resistant prostate cancer | ZEN003694 in combination with enzalutamide | Outcome measure: dose escalation and dose confirmation; PSA response rate | https://clinicaltrials.gov/ct2/show/NCT02711956?term=BET+inhibitor&cond=CRPC&draw=2&rank=3 (30 October 2021) | |
Birabresib (MK-8628/OTX015) | | BET Bromodomain | Ib (NCT02259114) | Patients with advanced solid tumors, including castration-resistant prostate carcinoma | Birabresib | Has dose-proportional exposure and a favorable safety profile; recommended phase II with a dose of 80 mg once daily with continuous dosing | [54] |
Palbociclib | | CDK4/6 | II (NCT02905318) | Patients with metastatic castration-resistant prostate cancer | Palbociclib | Expected completion: 21 May 2022. Outcome measure: clinical benefit rate; PSA decline ≥ 50% | https://clinicaltrials.gov/ct2/show/NCT02905318?term=CDK+inhibitor&cond=CRPC&draw=2&rank=3 (30 October 2021) |
Trametinib | | MEK1/2 | II (NCT02881242) | Patients with metastatic castration-resistant prostate cancer | Trametinib | Expected completion: 31 January 2023. Outcome measure: PSA response rate; response rate assessed by RECIST criteria; overall survival. | https://clinicaltrials.gov/ct2/show/NCT02881242 (30 October 2021) |
CEP-11981 (ESK981) | | Tyrosine kinase | II (NCT04159896) | Patients with metastatic castration-resistant prostate cancer | ESK981 plus nivolumab | Expected completion: 1 March 2022. Outcome measure: the prostate specific antigen (PSA) >= 50% response rate; the safety and tolerability of ESK981 plus nivolumab | https://clinicaltrials.gov/ct2/show/NCT04159896?term=Tyrosine+kinase+inhibitor&cond=CRPC&draw=2&rank=1 (30 October 2021) |
CEP-11981 (ESK981) | Tyrosine kinase | II (NCT03456804) | Patients with metastatic castration-resistant prostate cancer | ESK981 | Expected completion: 31 October 2022. Outcome measure: PSA decline of >=50% (PSA50); PSA progression free survival (PFS); Time to PSA response | https://clinicaltrials.gov/ct2/show/NCT03456804?term=Tyrosine+kinase+inhibitor&cond=CRPC&draw=2&rank=2 (30 October 2021) | |
masitinib | | Tyrosine kinase | III (NCT03761225) | Patients with metastatic castration-resistant prostate cancer | Masitinib plus docetaxel | Outcome measure: progression free survival (PFS); overall survival (OS) | https://clinicaltrials.gov/ct2/show/NCT03761225?term=Tyrosine+kinase+inhibitor&cond=CRPC&draw=2&rank=3 (30 October 2021) |
Cabozantinib (XL184) | | Tyrosine kinase | I (NCT01683994) | Patients with metastatic castration-resistant prostate cancer | Cabozantinib plus docetaxel and prednisone | The median time to progression and overall survival time were 13.6 and 16.3 months; cabozantinib is safely added to docetaxel/ prednisone with possible enhanced efficacy | [55] |
lapatinib | | HER2 | II (NCT00246753) | Patients with castration-resistant prostate cancer | lapatinib | Show single agent activity in CRPC patients as evaluated by PSA | [56] |
2. Serine/Threonine Kinase and Their Therapeutic Implications
2.1. IκB Kinases (IKKs)
2.2. TANK-Binding Kinase 1 (TBK1)
2.3. Protein Kinase A (PKA)
2.4. PIM Kinase
2.5. Tumor Progression Locus 2 (Tpl2)
2.6. NEK6
2.7. Glycogen-Synthase-Kinase 3β (GSK-3β)
2.8. T-LAK Cell-Originated Protein Kinase (TOPK)
2.9. Cyclin-Dependent Kinases (CDKs)
2.10. Bromodomain (BRD)-Containing Kinases (BETs)
2.11. Aurora Kinase A (AURKA)
2.12. AMP-Activated Protein Kinase (AMPK)
2.13. Mitogen-Activated Protein Kinase (MAPK) and Jun Kinase (JNK)
2.14. Phosphatidylinositol-3-Kinase (PI3K)/AKT
2.15. Polo-Like Kinase 1 (PLK1)
2.16. LIM-Domain Kinase-2 (LIMK2)
3. Tyrosine Kinase and Their Therapeutic Implications
3.1. The Receptor Tyrosine Kinases (RTKs)
3.2. The Non-Receptor Tyrosine Kinases (NRTKs)
4. Lipid Kinases and Their Therapeutic Implications
4.1. Phosphatidylinositol 4-Phosphate 5-Kinase Type 1α (PIP5K1α)
4.2. Sphingosine Kinases (SKs)
5. Carbohydrate Kinases and Their Therapeutic Implications
5.1. Hexokinase
5.2. Phosphofructokinase (PFK)
6. Other Kinases and Their Therapeutic Implications
6.1. Riboflavin Kinases (RFK)
6.2. Thymidine Kinase
7. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Zhong, S.; Peng, S.; Chen, Z.; Chen, Z.; Luo, J.-L. Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer. Pharmaceutics 2022, 14, 498. https://doi.org/10.3390/pharmaceutics14030498
Zhong S, Peng S, Chen Z, Chen Z, Luo J-L. Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer. Pharmaceutics. 2022; 14(3):498. https://doi.org/10.3390/pharmaceutics14030498
Chicago/Turabian StyleZhong, Shangwei, Shoujiao Peng, Zihua Chen, Zhikang Chen, and Jun-Li Luo. 2022. "Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer" Pharmaceutics 14, no. 3: 498. https://doi.org/10.3390/pharmaceutics14030498