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|TK Tyrosine Kinase|
|Key Members||ABL1, EGFR, HER2, FGFR1, JAK1, c-KIT, SRC|
|Chemical Inhibitors||AG-1478, AG-1517, AG-879, Apigenin, Genistein, Src I1, Lestaurtinib|
HER2 and EGFR are receptor tyrosine kinases (RTKs), which have well defined roles in lung and breast cancer. These kinases normally initiate multiple downstream signaling pathways. Given their pivotal roles in activating multiple signaling events, hyperactivation or overexpression of HER2 and EGFR lead to HER2-positive breast cancer and non-small cell lung cancer (NSCLC) respectively. Fortunately, their cell-surface localization at the makes RTKs amenable to pharmaceutical intervention by monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs).
|CAMK Calmodulin/Calcium Regulated Kinase|
|Key Members||AMPK α1, CaMK1, CHK1, DAPK1|
|Chemical Inhibitors||Dorsomorphin, BML-277|
CAMKs mediate many of the second messenger effects of Ca2+. AMPK and CAMK2 are members of the CAMK family that are implicated in metabolic disease, cancer, learning and heart disease. AMPK is a metabolic regulator that is activated when ATP levels are low. Interestingly, the incidence of cancer is reduced in Type 2 diabetes patients who are treated with treated with metformin, an AMPK activator – providing an opportunity for cancer prevention and therapy. CAMK2 plays a part in integrating short-term and long-term memories and is therefore called the “memory molecule”. CAMK2 is also promotes contractile strength of cardiac muscle and too much signaling through this kinase results in high blood pressure and cardiac hypertrophy.
|CMGC CDK, MAPK, GSK3 and CLK|
|Key Members||ERK1, p38α, CDK1, HIPK1, JNK1|
|Chemical Inhibitors||Doramapimod, JX-401, Alsterpaullone, SP-600125|
CMGC kinases preferentially phosphorylate proline-rich target sequences. Because of their essential role in cell cycle regulation, CDKs are amongst the most studied members of the CGMC family. Dysregulated CDK function gives rise to abnormal cell growth, which leads to cancers. Efforts to target CDKs in cancer therapy have revealed that these enzymes can compensate for one another, leading to little or no effect when inhibiting a single kinase. Current strategies involve designing inhibitors that are effective against multiple CDKs to address this issue.
|AGC Protein Kinase A, G, and C|
|Key Members||AKT, P70S6K, PKAc, PKCa, PKN1, SGK1|
|Chemical Inhibitors||Deguelin, NPC-15437, LYS6K2|
AGC kinases are categorized based upon similarities in their kinase domains. PDK1 is an AGC kinase, which is required for phosphorylating many of its fellow AGC members. One of its substrates is AKT1/PKBα, a central node in cell signaling for growth factors, cytokines, and other stimuli. AKT1 turns on programs for cell survival and proliferation, a property that also promotes tumor cell survival and resistance to apoptosis. AKT1 remains an elusive target for inhibition because other AGC kinases are able to compensate when AKT1 function is lost.
|STE Homologs of the yeast STE7, STE11 and STE20|
|Key Members||ASK1, MEK1, MEKK1, PAK1, HPK1, TAOK1, MST1|
STE kinases are named after the yeast sterile20 (Ste20) ser/thr kinase. The STE subfamily includes many enzymes involved in MAP kinase signaling, including the mammalian Ste20-like kinases (MSTs). There are five MSTs in humans: MST1 (STK4), MST2 (STK3), MST3 (STK24), MST4 (STK26), and YSK1 (STK25). MSTs 1 and 2 are potent activators of cell proliferation and MSTs 3 and 4 regulate cytoskeletal control and cell migration. Not surprisingly, mutations and fusions of MSTs have been observed in cancers. Aberrant MSTs 1 and 2 are connected to the rare cancer, mesothelioma and MSTs 3 and 4 promote metastasis in aggressive breast cancer subtypes.
|TKL Tyrosine Kinase-Like|
|Key Members||ALK1, BRAF, IRAK1, LRRK2, MLK1, RIPK1, TGFBR1|
|Chemical Inhibitors||GW-5074, Sorafenib, ZM-336372|
The TKL subfamily is a divergent group of kinases, which share sequence similarity to the TKs. TKL is divided into several subgroups, including the IL1 Receptor Associated Kinases (IRAKs) and Receptor Interacting Protein Kinases (RIPKs). As effectors of Toll-like receptors (TLRs), IRAKs and RIPKs activate innate and active immune responses. IRAK4 deficiency provides protection from developing rheumatoid arthritis (RA), prompting the development of drugs IRAK4-targeted drugs to treat autoimmune diseases. RIPKs 1 and 3 are instrumental inhibiting and triggering necroptosis, a form of cell death that causes leakage of cellular contents. Products of necroptosis are ligands for TLRs; thus, driving a feed-forward mechanism that promotes inflammation.
|CK1 Casein Kinase 1|
|Key Members||CK1alpha1, CK1gamma1|
The CK1 group of ser/thr kinases regulate cell differentiation, proliferation, cytoskeleton dynamics, chromosomal segregation, DNA repair and circadian rhythms. CK1 has seven isoforms and these are localized to various intracellular regions including the nucleus, where it directly interacts with the mitotic spindle to regulate the cell cycle. CK1 α, δ, and ε activate the tumor suppressor p53 to ensure centrosome integrity and genomic stability. Dysregulation or deletion of CK1 isoforms leads to neurodegenerative diseases and many types of cancers.
|RGC Receptor Guanylate Cyclases|
|Key Members||NPR1, NPR2|
RGC kinases are single-pass transmembrane receptors that have a guanylate cyclase enzyme domain and an inactive protein kinase-like domain. The RGC kinases NPR1 and NPR2 serve as the receptors for BNP and ANP, ligands that are secreted during periods of cardiac stress. Not surprisingly, ANP and BNP levels are established biomarkers for cardiovascular diseases. NPR1/2 signaling regulates blood pressure by mitigating the effects of excess water, sodium and fat. Recently, NPR1 has been implicated in the development of cancer via its role in promoting angiogenesis recruiting stem cells.
|Key Members||ADCK1, ATM, ATR, BCR, PTK9, TAF1|
Eukaryotic Protein Kinases (ePKs) represent the majority of kinases in humans. The atypical kinases are so-named because their catalytic domains lack similarity to those of ePKs. There are several medically relevant atypical kinases, such as BCR and the PDHKs. The constitutively active kinase BCR-ABL is found in the vast majority of chronic myelogenous leukemia (CML) patients, providing the rationale for producing TKIs against BCR-ABL and mutant variants of the fusion protein that provide secondary resistance. PDHKs regulate mitochondrial metabolism by inhibiting the Krebs cycle, which makes PDHK an excellent target for managing metabolic diseases, such as diabetes.
|Key Members||AURORA A, IKKalpha, NEK1, PI3K (p110 alpha), RIOK1, WNK1|
|Chemical Inhibitors||PKC-412, PX-866, LY-294002, STO-609|
There are many kinases that cannot be classified within the conventional subfamilies. These “other” kinases include notable groups, such as the aurora kinases. There are three aurora kinases in humans and they are essential for regulating various aspects of mitosis, including: checkpoint monitoring, spindle assembly, centrosome alignment and cytokinesis. Dysregulation of aurora kinases results in mitosis-related defects, including cells that are aneuploid, polyploid or multinucleate. With their implications in chromosomal instability, aurora kinases are being targeted for the treatment of solid and hematological cancers.