Protein kinases are the enzymes that catalyzes the transfer of γ-phosphate group from ATP to protein residues containing hydroxyl groups and has an important role in cell growth, proliferation, and differentiation. The human kinome comprises ~535 protein kinases. Mutations / Dysregulation of protein kinases are linked to various diseases, particularly in cancer, also protein kinases are the most widely studied cancer therapeutic targets, with a large number of protein kinase inhibitors are approved in Cancer and another large numbers are in active development.
Further, according to the substrate residues, protein kinases can be classified as tyrosine kinases (including both receptor and nonreceptor tyrosine kinases), serine/threonine kinases, and tyrosine kinase-like enzymes.
Similarly, Kinase Inhibitors can be classified into different categories by using many ways. According to classification system based upon the structures of their drug-enzyme complexes proposed by Roskoski (in 2016), protein kinase inhibitors are classified into six types (Type-I–VI).
Type-I inhibitors bind to the active conformation of the kinase (DFG-Asp in, αC-helix in). Type-I½ inhibitors bind to a DFG-Asp in inactive kinase conformation with αC-helix out, while type-II inhibitors bind to a DFG-Asp out inactive conformation. These types of inhibitors occupy part of the adenine binding pocket and form hydrogen bonds with the hinge region connecting the small and large lobes of the enzyme. Among them, type-I½ and type-II antagonists can be further divided into A and B subtypes. Type A inhibitors extend past the Sh2 gatekeeper residue into the back cleft, while type B inhibitors fail to extend into the back cleft. The possible importance of this difference is that type A inhibitors have longer residence times compared with type B inhibitors when binding to their targets. Type III and type IV kinase inhibitors are allosteric in nature. Type III inhibitors restrain kinase activity by binding to an allosteric site, which is in the cleft between the small and large kinase lobes adjacent to the ATP-binding pocket.
Contrariwise, type IV inhibitors bind outside of the cleft. Moreover, the bivalent molecules that span two distinct regions of the kinase domain are type V inhibitors. Type-I–V inhibitors are all reversible. In contrast, compounds that bind covalently with the kinase active site are called type VI inhibitors (irreversible kinase inhibitors).
RECEPTOR TYROSINE KINASE INHIBITORS
1. Anaplastic Lymphoma Kinase (ALK) inhibitors
Anaplastic lymphoma kinase (ALK) encoded by the ALK gene is a single transmembrane tyrosine kinase of the insulin receptor family. ALK can activate multiple downstream signaling pathways and has an important role in the development of the nervous system.
Role in Cancer – Activation of ALK through point mutations or chromosomal rearrangements has been identified in multiple human cancers such as anaplastic large cell lymphoma, diffuse large B-cell lymphoma (DLBCL), inflammatory myofibroblastic tumor and non-small cell lung cancer (NSCLC).
Also, Fusion of echinoderm microtubule-associated protein-like 4 with ALK (EML4-ALK) in NSCLC, with this rearrangement of the ALK gene has been detected in ~3–7% of patients with NSCLC. EML4-ALK gene fusion is initiated by inversion in the short arm of chromosome 2, which juxtaposes the N-terminal of the EML4 promoter and the kinase domain of the ALK gene, ultimately leading to ligand-independent constitutive activation of ALK and promoting cancer cell proliferation and survival.
Several other ALK gene fusions, such as NPM-ALK, ATICALK, and RANBP2-ALK, have also been discovered, these rearrangements define a specific subgroup of cancerous patients that can be treated with selective ALK inhibitors.
Approved ALK Inhibitors -
First Generation ALK Inhibitors –
Crizotinib (Xalkori – Pfizer) Approved in 2011.
Crizotinib targets multiple tyrosine kinases including ALK, cellular mesenchymal epithelial transition factor (c-Met), and protooncogene tyrosine-protein kinase reactive oxygen species (ROS).
Unfortunately, most patients develop resistant mutations to crizotinib within 12 months, especially L1196M and G1269A mutations, which can lead to relapse, since drug has poor penetration through BBB and thus central nervous system (CNS) emerge as the most common relapse site in NSCLC patients.
Second Generation ALK Inhibitors –
Ceritinib (Zykadia – Novartis) Approved in 2014
Ceritinib is a multikinase inhibitors and is more potent than crizotinib and has doubled progression-free survival (PFS) compared with chemotherapy in clinical studies.
Alectinib (Alecensa – Roche/ Chugai) Approved in 2015
Alectinib can penetrate CNS thus has advantages over both crizotinib and ceritinib, and has shown inhibitory activity against several crizotinib or ceritinib-resistant ALK mutations such as L1196M, G1269A, C1156Y, and F1174L.
Brigatinib (Alunbrig – Ariad Pharmaceuticals) Accelerated approval by the FDA in 2017 as second line therapy for patients with ALK-positive metastatic NSCLC.
Brigatinib is a multikinase inhibitor targeting ALK, ROS, IGF1R, EGFR and FLT3 and in many cases in due course of time the drug also develops Secondary ALK kinase domain mutations, such as the G1202R, V1180L and I1171T mutants, are the most common resistance mechanisms.
Entrectinib (Rozlytrek – Roche) Approved in 2019
Entrectinib is the multi kinase TRKA/B/C/ROS1/ALK inhibitor approved for Solid tumors with NTRK fusion protein.
Third Generation ALK Inhibitors –
Lorlatinib (Lorbrena – Pfizer) Approved in 2018.
Lorlatinib is an oral ATP-competitive brain penetrant inhibitor of ALK/ROS1 and as a third-generation ALK inhibitor, targets all recognized ALK mutations (except L1198F mutation).
ALK Inhibitors in Clinical and Preclinical Development -
Future Directions in Developing ALK Inhibitors -
Till date, ALK inhibitors have been developed to the third generation. Drug-resistant mutations are the major obstacles, which limits the clinical efficacy of ALK inhibitors.
Combining ALK inhibitors with other targeted therapies such as a mitogen-activated protein kinase (MAPK) inhibitor, cyclin-dependent kinase (CDK) inhibitor (ceritinib with ribociclib), mammalian target of rapamycin (mTOR) inhibitor (ceritinib with everolimus) and heat-shock protein 90 inhibitor has been assessed in a number of trials. Since the expression of programmed death-ligand 1 is reportedly associated with EML4-ALK, combined treatments of ALK and immune checkpoint inhibitors have also been evaluated in ALK-positive NSCLC.
In addition to kinase inhibitors, degrading carcinogenic proteins using proteolysis targeting chimera (PROTAC) technology may be an effective anti-cancer strategy going forward. The PROTACs MS4077 and MS4078 designed by Zhang et al. have shown great potency in reducing ALK fusion protein in preclinical studies, suggesting a new approach to drug discovery targeting ALK.
2. c-Met inhibitors
Cellular-mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is encoded by the MET proto-oncogene located on chromosome 7q21-31. .
Role in Cancer – Activation .
Also, .
Several.
3. EGFR Inhibitors
Cellular-mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is encoded by the MET proto-oncogene located on chromosome 7q21-31. .
Role in Cancer – Activation .
Also, .
Several.
4. FLT3 Inhibitors
Cellular-mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is encoded by the MET proto-oncogene located on chromosome 7q21-31. .
Role in Cancer – Activation .
Also, .
Several.
5. VEGFR/FGFR/PDGFR Inhibitors
Cellular-mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is encoded by the MET proto-oncogene located on chromosome 7q21-31. .
Role in Cancer – Activation .
Also, .
Several.
6. TRK Inhibitors
Cellular-mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is encoded by the MET proto-oncogene located on chromosome 7q21-31. .
Role in Cancer – Activation .
Also, .
Several.
