Kinase는 암 연구의 필수적인 부분이며, SignalChem은 Kinase 분야에서의 우수한 지위를 바탕으로 연구자들의 지속적인 연구에 가치를 더할 수 있도록 보장합니다. SignalChem에는 1,000 여개 이상의 자체 제조 Kinase를 보유하고 있으며, 모든 제품들은 엄격한 QA/QC 과정을 통과한 일관된 품질의 Kinase들만 제공하고 있습니다. Active Kinases 제품 라인은 적용 범위 측면에서 세계에서 가장 포괄적인 제품 중 하나로, 많은 제약 회사들의 약물 발견 프로그램에 사용되고 있습니다.
Kinase란?
Kinases are one of the largest classes of enzymes, with over 500 family members, they constitute ~2% of all human genes. Kinases catalyze the transfer of the γ-phosphate from ATP to acceptor hydroxyl groups on amino acids (such as serine, threonine and tyrosine) in proteins or glycosyl moieties in lipids. This process, termed phosphorylation, is the most efficient way to regulate protein and lipid function in cells and is considered a key step in posttranslational modification of proteins and lipid kinases. Phosphorylation usually results in a functional change of the substrate or target protein such as a change in its enzyme activity, cellular localization, or association with other proteins. Protein and lipid kinases are not only present in humans, but also are readily found in bacteria and plants. Of the over 500 human kinases, majority of kinases belong to a single superfamily whose catalytic domains are related in sequence. These kinases can be clustered into groups, families and sub-families based on the increasing sequence similarity and biochemical function. ‘Atypical’ kinases have no sequence similarity to typical kinases, but are known or predicted to have enzyme activity. There are also many kinases that cannot be classified within the framework of conventional subfamilies, these kinases are grouped in ‘other kinases’.
Protein Kinases
Protein kinases act on proteins by phosphorylating them on their serine, threnine, tyrosine, or histidine residues. Phosphorylation can modify the function of protein in many ways. It can increase or decrease a protein’s activity, stabilize it or mark it for destruction, localize it in specific cellular compartment. Protein kinases make up the majority of all kinases and are widely studied. Protein kinase activity is highly regulated, allowing it to participate in diverse signaling pathways within the cell. Growth factors, cytokines and hormones can turn on or off the activity of various protein kinases, thereby regulating the function of downstream substrate proteins. Due to the key regulatory function of protein kinases on cellular pathways, they are often highly associated with diseases. Defective signaling by protein kinases accounts for more than 400 human diseases. Today, these targets are still being actively pursued for therapeutic intervention. Research geared toward targeting protein kinases by small molecule inhibitors or neutralizing antibodies has been extremely beneficial in the treatment of various human diseases such as cancer. Over 160 protein kinases have been shown to be associated with human diseases, and numerous kinases have been found as the drug targets which are being developed and under approval by the FDA.
Sub-Category Glossary
Members of the AGC kinases are categorized based upon the homology of their catalytic kinase domain. PDK1 is an AGC kinase, which is required for phosphorylating many of its fellow AGC members. One of its targets is AKT1/PKBα, another AGC family member which acts as a central node in cell signaling for growth factors, cytokines, and other stimuli, turning on programs for cell survival and proliferation. Hyperactive AKT1 signaling promotes tumor cell survival and resistance to apoptosis. Despite the relevance of AKT1 towards tumorigenesis, efforts to selectively target this kinase face the challenge of compensation by other AGC family members in the face of AKT inhibition.
Ca2+/Calmodulin-dependent kinases (CaMKs) are serine/threonine kinases that mediate many of the second messenger effects of Ca2+ via their conserved C-terminal Ca2+/Calmodulin-binding domains. CAMKs are indispensable metabolic sensors, which can respond to ion flux or concentration gradients to elicit programs that regulate cell migration, cell cycle and cell polarity. Well-known CAMKs include AMP-activated protein kinase (AMPK) and CAMK2 (CAMKII). AMPK is activated in response to low cellular ATP levels. As a metabolic regulator, AMPK is an important facet of how cancer cells use energy. CAMK2 is widely expressed and it is required for a wide range of processes, from learning to heart function. Due to its role in translating information from short-term to long-term memory, CAMK2 is often referred to as the “memory molecule”. In the synapses of neurons, long-term potentiation (LTP) elicits Ca2+ influx, activating CAMK2. In turn, the kinase phosphorylates proteins to reinforce LTP and strengthen the synapse. In the heart, CAMK2 activity is promotes contractile strength of the cardiac muscle. Thus, hyperactivation of CAMK2 can lead to high blood pressure and cardiac hypertrophy. Due to their wide range physiological roles, members of the CAMK protein kinase family are excellent targets for pharmaceutical intervention. Currently, small molecule AMPK activators are under evaluation for cancer prevention and therapy and CAMK2 inhibitors are showing promise as agents for treating hypertension and other heart-related conditions.
CK1 is a group of serine/threonine kinases that regulate cell differentiation, proliferation, cytoskeleton dynamics, chromosomal segregation, DNA repair and circadian rhythms. There are seven isoforms of CK1. CK1 α, δ, and ε activate the tumor suppressor p53 to ensure centrosome integrity and genomic stability. CK1 isoforms are localized to various regions within the cell, including the nucleus, where the directly interacts with the mitotic spindle to regulate the cell cycle. Dysregulation or deletion of CK1 isoforms have been linked to neurodegenerative diseases and many types of cancers.
CMGC kinases are a family of enzymes that preferentially phosphorylate proline-rich target sequences. CDKs are amongst the most studied members of the CGMC family because of their essential roles in regulating the cell cycle. CDK dysregulation is linked to many types of cancers through promoting abnormal cell growth. Efforts to selectively inhibit individual CDKs in cancer have revealed that these enzymes can compensate for one another, leading to little or no therapeutic effect in tumors. Current strategies involve designing inhibitors that are effective against more than one CDK to circumvent this problem.
STE kinases are named after its founding member, the yeast sterile20 (Ste20) serine/threonine kinase. The STE subfamily includes many enzymes involved in MAP kinase signaling, including the mammalian Ste-20 like kinases (MSTs). There are five MSTs in humans: MST1 (STK4), MST2 (STK3), MST3 (STK24), MST4 (STK26), and YSK1 (STK25). MST1 and 2 are potent activators of cell proliferation and MST3/4 regulates cytoskeletal control and cell migration. Not surprisingly, mutations and fusions of MSTs have been found in cancers. Aberrant MST1/2 activity is connected to the rare cancer, mesothelioma and MST3/4 promotes metastasis in aggressive subtypes of breast cancer.
Tyrosine kinases represent the largest class of protein kinases. These enzymes can be further sub-categorized into receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (non-receptor tyrosine kinases; NRTKs). RTKs often act as cell surface receptors that are essential for regulating many fundamental cellular processes, including cell growth, differentiation, migration and survival. Dysregulated RTK signaling plays a prominent role in the development and progression of many types of cancers. Therefore, RTKs are amongst the most popular targets for therapeutic intervention in oncology. They are localized to within the plasma membrane, RTKs can be targeted by monoclonal antibodies (mAbs) and small molecule kinase inhibitors (SMKIs). In the span of twenty years, RTK-targeted therapies have led to a paradigm shift in the way many types of cancers are treated; benefiting patients with decreased side-effects and increased survival rates. Several of the larger subfamilies within the NRTKs include the SRC, JAK, TEC and ABL kinases. Aberrant activation of NTRKS can lead to the development of disease. The Philadelphia chromosome refers to a reciprocal translocation between chromosomes 9 and 22 that yields the oncogenic BCR-ABL fusion gene. This chromosomal rearrangement is found in most patients with chronic myelogenous leukemia (CML), and in some patients with acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Since the FDA approval of Gleevec and other related drugs, the survival rates of CML has doubled.
The TKL subfamily share sequence similarity to tyrosine kinases. This divergent group includes several smaller groups, including IL1 Receptor Associated Kinases (IRAKs) and Receptor Interacting Protein Kinases (RIPKs). IRAKs and RIPKs activate innate and active immune responses as effectors of Toll-like receptors (TLRs). 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 condition which causes leakage of cellular contents. In turn, byproducts of necroptosis are recognized by TLRs; thus driving a mechanism that promotes inflammation in a feed-forward manner.
Eukaryotic Protein Kinases (ePKs) include most of the kinase enzymes in humans. Atypical kinases differ from stereotypical ePKs in the sequence of their catalytic domains. Atypical kinases include several medically relevant enzymes, such as BCR and the PDHK subgroups. The constitutively active kinase BCR-ABL is a hallmark of Chronic Myeloid Leukemia (CML). Numerous TKIs have been developed to specifically target this BCR-ABL and its TKI resistant secondary mutant variants. PDHKs regulate mitochondrial metabolism by inhibiting the Krebs cycle, making PDHK an attractive target for therapies to manage metabolic disorders such as diabetes.
There are many kinases that cannot be classified within the framework of conventional subfamilies. These “other” kinases include notable groups, such as the Aurora kinases. There are three Aurora kinases in humans. These serine/threonine kinases are essential for regulating various aspects of mitosis, including: checkpoint monitoring, spindle assembly, centrosome alignment and cytokinesis. Thus, defects in Aurora kinases are connected to the production of aneuploid, polyploid and multinucleate cells. Aurora kinases are emerging as important targets for the treatment of many types of solid and hematological cancers.
Lipid Kinases
Lipid kinases phosphorylate lipids in the cells, both on the plasma membrane as well as the membrane of the organelles. The addition of phosphate groups can change the reactivity and localization of the lipid and can be used in signal transmission. Lipid kinases regulate a wide variety of cellular functions, including cell growth, proliferation, differentiation, mobility, intracellular trafficking, and survival. PI3K pathway is believed to be deregulated in a wide spectrum of human cancers (1). Kinases in this pathway such as PI3K alpha become a prime target for the development of anticancer drugs. Diacylglycerol (DG) kinase (DGK) modulates the balance between the two signaling lipids, DG and phosphatidic acid (PA), by phosphorylating DG to generate PA. Mammalian DGK consists of ten isozymes. DGKs has emerged as new drug targets for a variety of diseases (2, 3).
- Yang I; Nie X; Ma X; Wei Y; Peng Y and Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Molecular Cancer 2019, 18:26
- Sakane F; Imai S.I; Kai M; Yasuda S and Kanoh H. Diacylglycerol kinases as emerging potential drug targets for a variety of diseases. Curr. Drug Targets 2008, 9(8):626-40
- Sakane F; Hoshino F; Ebina M; Sakai H and Takahashi D. The role of diacylglycerol kinases in cancer cell proliferation and apoptosis. Cancers 2021, 13:5190
Carbohydrate Kinases
Carbohydrate kinases activate a wide variety of monosaccharides by adding a phosphate group (usually ATP) to a free sugar hydroxyl. This modification is fundamental to saccharide utilization and to maintain cellular function. Defects in carbohydrate phosphorylation have been associated with several diseases such as autosomal galactokinase deficiency (1). Carbohydrate kinases, for example galactokinase, are attractive targets for drug development and therapeutics (2).
- Hennermann, J.B.; Schadewaldt, P.; Vetter, B.; Shin, Y.S.; Monch, E.; Klein, J. Features and outcome of galactokinase deficiency in children diagnosed by newborn screening. J. Inherit. Metab. Dis. 2011, 34, 399–407
- Tang, M.; Wierenga, K.; Elsas, L.J.; Lai, K. Molecular and biochemical characterization of human galactokinase and its small molecule inhibitors. Chem. Biol. Interact. 2010, 188, 376–385.
Mutant Kinases
Members of the kinase superfamily are key regulators of pivotal cell signaling pathways. Genetic alterations in protein kinases compromise their biological functions resulting in deregulated cellular pathways such as apoptosis, cell cycle regulation, proliferation, angiogenesis, differentiation, cellular metabolism. Mutations in kinase-encoding genes have been observed in many pathological conditions, ranging from cancer, inflammatory disorders, cardiovascular diseases to neurodegeneration (1). Furthermore, mutations of certain kinases have been linked to acquired drug resistance. As a result, mutant kinases quickly established themselves as important drug targets and have been the focus of drug discovery and development efforts (2). In an effort to support the advancement of next generation of kinase-targeted therapeutic programs, SignalChem has developed and manufactured over 350 clinically relevant active kinase mutants, representing the most comprehensive list of this class of proteins in the industry.
- Kumar R et al., CancerDR: cancer drug resistance database. Sci Rep. 2013;3:1445. doi: 10.1038/srep01445.
- Torkamani, A., Verkhivker, G., & Schork, N. J. (2009). Cancer driver mutations in protein kinase genes. Cancer Letters, 281(2), 117–127. http://doi. org/10.1016/j.canlet.2008.11.008
