In 2001, the FDA approved Imatinib, the first drug to be developed by targeting a specific protein kinase and the first molecularly targeted drug to fight cancer. It was considered a milestone in the development of kinase inhibitors. Since then, more than 70 novel drugs have been approved, and kinase inhibitors have become the dominant drug in cancer treatment for some time and exert a major impact on the existing therapies for some non-cancer diseases as well.
Kinase families and targets of approved drugs
Protein phosphorylation and dephosphorylation mediated by kinases and phosphatases act as regulatory switches in numerous cellular physiological processes, such as cell proliferation, apoptosis, subcellular migration, inflammation, and metabolism. The human kinase group consists of 560 protein kinases, which are mainly divided into 8 categories, such as tyrosine kinases (TK) and atypical protein kinases. Kinase inhibitors target 21 kinase families, accounting for about 20% of the human kinase group. Among them, TK, TKL, STE, CMGC and AGC are the most thoroughly studied kinases, and atypical protein kinases and lipid kinases each have one family distribution. Even the most studied TK family has 70% of its targets unexplored, so there is still plenty of room for kinase target development.
Kinase inhibitors that target cancers
Translocation or mutation leads to abnormal kinase activation, which drives the development of cancer. The identification of these driving forces has facilitated the development of molecularly targeted cancer therapies. A pioneering example is the creation of Imatinib by the identification of BCR-ABL translocation, which leads to elevated tyrosine kinase activity and ultimately drives CML. The indications of 61 kinase inhibitors (89%) and 10 mAbs (100%) currently approved by the FDA all include cancer.
Lung cancer has the highest mortality rate among all cancers, and 80-85% of lung cancers are non-small cell lung cancer (NSCLC). More than 20% of drugs (19 kinase inhibitors and 2 mAbs) are currently approved for the treatment of NSCLC.
EGFR plays an important role in tumor growth and progression. The first generation of kinase inhibitors targeting the EGFR for NSCLC includes Gefitinib and Erlotinib. Since genetic mutations often lead to drug resistance, second-generation inhibitors targeting mutations, including Afatinib and Dacomitinib, as well as third-generation inhibitors Osimertinib, have been developed and marketed.
ALK rearrangement can produce abnormal ALK protein, which promotes cancer cell proliferation and migration, and ALK rearrangement occurs in 5% of NSCLC patients. ROS1 is closely related to ALK and is also a target of ALK inhibitors. ROS1 rearrangement occurs in 1-2% of NSCLC patients. Crizotinib, the first ALK inhibitor, was approved in 2011, followed by the development of second- and third-generation inhibitors including four that simultaneously target ALK & ROS1, namely Ceritinib, Alectinib, Brigatinib, and Lorlatinib.
Targeting anti-tumor angiogenesis is an important anticancer strategy, and many kinase inhibitors target angiogenic signaling pathways driven by VEGFR, PDGFR, KIT, FGFR, and MET. Five of the FDA-approved kinase inhibitors and two rapalogue inhibitors (Temsirolimus and Everolimus) treat renal cell carcinoma by inhibiting VEGFR signaling pathway and downstream mTOR of VEGFR, respectively
FDA-approved kinase inhibitors also target various intracellular kinases, with CDK4 and CDK6 playing important roles in cell division. Palbociclib, Ribociclib, and Abemaciclib targeting CDK4/6 have become commonly used drugs for cancer, especially breast cancer. The CDK4/6 inhibitor Trilaciclib was approved in 2021 for the conservative treatment of small cell lung cancer with bone marrow.
Substantial progress has also been made in the development of inhibitors targeting PI3Kδ to treat various lymphoma, kinase inhibitors targeting other RTK proteins, and targeted kinases to treat hematological malignancies.
Kinase inhibitors targeting other non-neoplastic diseases
Many kinases are involved in the regulation of immune responses. More than 13% of kinase inhibitors have been approved for immune system-related indications, mainly autoimmune and inflammatory diseases.
JAKs are the second messengers of many cytokines, such as interferons and interleukins, and play an important role in T helper (TH1, TH2, and TH17) immune responses. Ruxolitinib, a JAK1 and JAK2 inhibitor, was approved by the FDA in 2011 for the treatment of moderate or high-risk myelofibrosis, the first kinase inhibitor to be applied not for cancer. Among autoimmune diseases, rheumatoid arthritis has the largest number of approved kinase inhibitors (5 in total), all of which selectively target the JAK subtype. In 2012, Tofacitinib, the first kinase inhibitor approved for rheumatoid arthritis, hit the market. Then came Baricitinib, Upadacitinib, Peficitinib and Filgotinib. JAK inhibitors are also being investigated for other immune-related diseases, such as Delgocitinib, the first approved for atopic dermatitis, which was approved in Japan in 2020.
SYK kinase is involved in both innate and adaptive immune responses. SYK kinase inhibitors are used to treat allergic and autoimmune diseases as well as hematological malignancies. For example, Ibrutinib and Ruxolitinib are approved for the prevention of organ transplant rejection and graft versus host disease, respectively. Fostamitinib is indicated in chronic immune thrombocytopenia and reduces antibody-mediated platelet destruction.
There are also several kinase inhibitors approved for indications other than cancer and immune diseases. The ROCK1/ROCK2 inhibitor Fasudil is used to treat cerebral vasospasm. Another ROCK1/ROCK2 inhibitor, Netarsudil, is used to treat glaucoma and ocular hypertension. The mTOR inhibitor Everolimus is used for the treatment of patients with partial epilepsy in tuberous sclerosis.
Conclusion
To date, data from clinical trials of small molecule inhibitors show that about 110 kinases are being developed as new targets. These targets, together with the 45 approved kinase inhibitors, account for only 30% of the human kinase group, so there is still tremendous space for the development of kinase inhibitors in the future.
Related Products:
| Tag | Name | CAS | Synonyms | Description |
| c-Kit | Imatinib | 152459-95-5 | CGP057148B; STI571 | Imatinib inhibits the SLF-dependent activation of wild-type c-kit kinase activity with a IC50 for these effects of approximately 0.1 μM. |
| EGFR | Gefitinib | 184475-35-2 | ZD-1839 | Gefitinib effectively inhibits all tyrosine phosphorylation sites on EGFR in both the high and low-EGFR-expressing cell lines including NR6, NR6M and NR6W cell lines. |
| EGFR | Erlotinib | 183321-74-6 | CP-358774; NSC-718781 | Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. |
| EGFR | Afatinib | 439081-18-2 | BIBW-2992 | Afatinib (BIBW2992) irreversibly inhibits EGFR/HER2 including EGFR(wt), EGFR(L858R), EGFR(L858R/T790M) and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively. |
| EGFR | Dacomitinib | 1110813-31-4 | PF-299804 | Dacomitinib is an orally bioavailable, highly selective, second-generation small-molecule inhibitor of the pan-epidermal growth factor receptor (EGFR) family of tyrosine kinases (ErbB family) with potential antineoplastic activity. |
| ALK | Crizotinib | 877399-52-5 | PF-02341066 | Crizotinib is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor. |
| ALK | Ceritinib | 1032900-25-6 | LDK-378; Zykadia; NVP-LDK378-NX | An anaplastic lymphoma kinase (ALK)-positive inhibitor used for the treatment of non-small cell lung cancer (NSCLC). |
| ALK | Alectinib | 1256580-46-7 | CH-5424802; AF-802; RG-7853; RO5424802 | Alectinib is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). |
| ALK | Brigatinib | 1197953-54-0 | AP26113 | Brigatinib is an orally active, potent and selective dual ALK/EGFR inhibitor. |
| ALK | Lorlatinib | 1454846-35-5 | PF-6463922 | Lorlatinib is an ATP-competitive ROS1/ALK inhibitor with potential antitumor activity. |
| mTOR | Temsirolimus | 162635-04-3 | CCI-779 | Temsirolimus potently inhibits mTOR kinase activity with IC50 of 1.76 μM, similar to that of rapamycin with IC50 of 1.74 μM. |
| mTOR | Everolimus | 159351-69-6 | RAD-001; Afinitor; Certican; Zortress; SDZ-RAD | Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) with an immunosuppressive activity which is comparable to that of rapamycin. |
| CDK | Palbociclib | 571190-30-2 | PD-0332991; Ibrance | Palbociclib is an orally available cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. |
| CDK | Ribociclib | 1211441-98-3 | LEE011; LEE 011; LEE-011; Kisqali | Ribociclib is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway. |
| CDK | Abemaciclib | 1231929-97-7 | LY-2835219 | Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway. |
| CDK | Trilaciclib | 1374743-00-6 | G1T28 | Trilaciclib is a CDK4/6 inhibitor with IC50 of 1 nM and 4 nM, respectively. |
| JAK | Ruxolitinib | 941678-49-5 | INCB018424 | Ruxolitinib is a potent and selective JAK1/2 inhibitor with IC50 values of 3.3 nM and 2.8 nM respectively in cell-free assays, and has > 130-fold selectivity for JAK1/2 versus JAK3. |
| JAK | Tofacitinib | 477600-75-2 | Tasocitinib; CP-690550 | Tofacitinib is an orally available JAK3 inhibitor (IC50 = 1 nM), exhibiting 20- and 100-fold less potency against JAK2 and JAK1. |
| JAK | Baricitinib | 1187594-09-7 | LY3009104; Olumiant | Baricitinib is a selective and orally bioactive inhibitor of JAK1 and JAK2. |
| JAK | Upadacitinib | 1310726-60-3 | UNII-4RA0KN46E0;ABT494 | Upadacitinib is a selective JAK inhibitor under the development of AbbVie. |
| JAK | Peficitinib | 944118-01-8 | ASP-015K | Peficitinib is a potent JAK inhibitor with IC50 values of 3.9, 5.0, 0.71 and 4.8 nM for JAK1, JAK2, JAK3 and TYK2 enzyme activities, respectively. |
| JAK | Filgotinib | 1206161-97-8 | GLPG-0634 | Filgotinib is a potent and selective JAK1 inhibitor exhibiting 30-fold selectivity over JAK2. |
| SYK | Ibrutinib | 936563-96-1 | PCI-32765 | Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). |
| ROCK | Fasudil | 103745-39-7 | AT-877; HA-1077 | Fasudil is a potent and selective Rho-kinase (ROCK) inhibitor and vasodilator. |
| ROCK | Netarsudil Mesylate | 1422144-42-0 | AR-11324 | Netarsudil is a Rho-associated protein kinase inhibitor. |
Related Targets:
| Name | Description |
| EGFR | The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases. |
| ALK | Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene. |
| VEGFR | Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis and angiogenesis. |
| PDGFR | Platelet-derived growth factor receptors (PDGFR) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor(PDGF) family. |
| FGFR | Activation of FGFRs (fibroblast growth factor receptors) has an essential role in regulating cell survival, proliferation, migration and differentiation. |
| mTOR | mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. |
| JAK | Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. |
| SYK | Spleen tyrosine kinase (Syk) is a cytoplasmic protein tyrosine kinase well known for its ability to couple immune cell receptors to intracellular signaling pathways. |
| ROCK | The Rho kinase (ROCK) isoforms, ROCK1 and ROCK2, were initially discovered as downstream targets of the small GTP-binding protein Rho. |