Pdgfr inhibitors of the small molecule immuno-oncology agent type

PDGFR inhibitors of the "small molecule immuno-oncology agents" type are novel drugs that have significantly expanded the spectrum of tumor therapeutics. These are competitive ATP inhibitors that target the ATP binding site of the PDGFR kinase and block the phosphorylation process. Small molecule immuno-oncology agents consist mainly of quinoxalines, quinazolines, anthraquinones and benzimidazoles. To distinguish them from peptide receptor blockers, they are called "small molecule immuno-oncology agents" or "small molecules" for short. With low antigenicity, small molecule immuno-oncology agents can overcome the disadvantages of therapeutic monoclonal antibodies. Furthermore, they can supplement existing therapeutic antibodies or chemotherapy and/or be used in combination with antibodies, whereby synergistic effects can be achieved.

More than 10 PDGFRα/β-multikinase antagonists have been approved for the treatment of diverse neoplastic diseases and interstitial pulmonary fibrosis:

• Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-Din).
• Type II inhibitors bind to their target with DFG-D pointing away from the active site (DFG-Dout).

PDGFR inhibitors of the small molecule immuno-oncology agent typeinhibit PDGF-induced signal transduction. Thus, they can downregulate proliferation signals, inhibit tumor angiogenesis and promote tumor cell apoptosis. However, PDGFR- kinase inhibitors often block not only one receptor kinase, but also other receptor tyrosine kinases such as BCR-ABL tyrosine kinase or KIT kinases in varying degrees of preference in addition to PDGFR kinase. For example, the tyrosine kinase preference for nilotinib is: BCR-ABL > PDGFR > KIT.

PDGFR- protein kinase inhibitors already approved or in advanced clinical trials:

• Imatinib: blocks c-kit receptor tyrosine kinase, BCR-ABL tyrosine kinase, and PDGFR. The tyrosine kinase preference for nilotinib is: BCR-ABL > PDGFR > KIT.
• Nilotinib: tyrosine kinase inhibitor with indication: in Philadelphia chromosome-positive chronic myeloid leukemia. The tyrosine kinase preference for nilotinib is: BCR-ABL > PDGFR > KIT.
• Pazopanib: tyrosine kinase inhibitor that inhibits multiple tyrosine kinases (VEGFR, PDGFR, KIT). Indication: renal cell carcinoma
• Radotinib: tyrosine kinase inhibitor that inhibits multiple tyrosine kinases (Bcr-Abl, VEGFR). Indication: chronic myeloid leukemia.
• Crenolanib (in clinical trials): Selective inhibitor of type III tyrosine kinases with nanomolar potencies against PDGFR (alpha-PDGFR and beta-PDGFR isoforms) and Fms-related tyrosine kinase 3 (FLT3). In addition to PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) at clinically achievable concentrations.
• Orantinib (in clinical trials): Selective inhibitor of tyrosine kinases (VEGFR, PDGFR, FGFR1) However, orantinib has no effect on EGF-stimulated EGFR tyrosine phosphorylation.
• Sunitinib: inhibitor of several tyrosine kinases (PDGFR, VEGFR, c-Kit). In addition, some serine-threonine kinases are also inhibited (multikinase inhibitors). Indication: metastatic gastrointestinal stromal tumors (GIST).
• Linifanib CAS number: 796967-16-3: Novel inhibitor of the VEGFR and PDGF receptor (PDGFR) family of tyrosine kinases. Indication: Patients with chemotherapy-naive advanced or recurrent NSCLC.

The PDGFR (PDGF-receptor) "platelet-derived-growth-factor-receptor" is a tyrosine kinase receptor with protein tyrosine kinase activity. It consists of an extracellular domain specifically recognized by PDGFs, an intermediate hydrophobic domain of a single-stranded sequence transmembrane and a peptide domain with tyrosine protein kinase activity at the intracellular C-terminus of the cell. When PDGF binds to its PDGF receptor, it activates and enhances the signal by specific dephosphorylation of tyrosine residues, promotes actin storage and performs physiological functions such as mitosis and chemotaxis. The overexpression of the PDGF and PDGFR families is closely related to a number of diseases such as malignant tumours, atherosclerosis, arterial restenosis and fibrosis. Currently, PDGF signal transduction is mainly reduced by inhibiting PDGFR and blocking its tyrosine kinase phosphorylation and downstream signal transduction.

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