Tyrosinekinase inhibitors rahul
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Transcript of Tyrosinekinase inhibitors rahul
May 1, 20231
TYROSINE KINASE INHIBITORS
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May 1, 2023dr rahul ts
Outline
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Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023
Protein Kinase
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Is kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation)
The phosphate is often taken from ATP
Phosphorylation - signals within a cell (signal transduction) and regulating cellular activity, such as cell division.
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Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023dr rahul ts
Categories of Protein Kinases
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1. Kinases that specifically phosphorylate tyrosine residues.
2. Kinases that phosphorylate serine and threonine residues.
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023
Tyrosine Kinase
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Is an enzyme that can transfer a phosphate group from ATP to a protein in a cell.
It functions as an "on" or "off" switch in many cellular functions.
The phosphate group is attached to the amino acid tyrosine on the protein.
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Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
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Tyrosine Kinase
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AATK; ABL; ABL2; ALK; AXL; BLK; BMX; BTK; CSF1R; CSK; DDR1; DDR2; EGFR; EPHA1; EPHA2; EPHA3; EPHA4; EPHA5; EPHA6; EPHA7; EPHA8; EPHA10;EPHB1; EPHB2; EPHB3; EPHB4; EPHB6; ERBB2; ERBB3; ERBB4; FER; FES; FGFR1; FGFR2; FGFR3; FGFR4; FGR; FLT1; FLT3; FLT4; FRK; FYN; GSG2; HCK;IGF1R; ILK; INSR; INSRR; IRAK4; ITK; JAK1; JAK2; JAK3; KDR; KIT; KSR1; LCK; LMTK2; LMTK3; LTK; LYN; MATK; MERTK; MET; MLTK; MST1R; MUSK; NPR1;NTRK1; NTRK2; NTRK3; PDGFRA; PDGFRB; PLK4; PTK2; PTK2B; PTK6; PTK7; RET; ROR1; ROR2; ROS1; RYK; SGK493; SRC; SRMS; STYK1; SYK; TEC; TEK;TEX14; TIE1; TNK1; TNK2; TNNI3K; TXK; TYK2; TYRO3; YES1; ZAP70
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023dr rahul ts
Tyrosine Kinase
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AATK; ABL; ABL2; ALK; AXL; BLK; BMX; BTK; CSF1R; CSK; DDR1; DDR2; EGFR; EPHA1; EPHA2; EPHA3; EPHA4; EPHA5; EPHA6; EPHA7; EPHA8; EPHA10;EPHB1; EPHB2; EPHB3; EPHB4; EPHB6; ERBB2; ERBB3; ERBB4; FER; FES; FGFR1; FGFR2;FGFR3; FGFR4; FGR; FLT1; FLT3; FLT4; FRK; FYN; GSG2; HCK;IGF1R; ILK; INSR; INSRR; IRAK4; ITK; JAK1; JAK2; JAK3; KDR; KIT; KSR1; LCK; LMTK2; LMTK3; LTK; LYN; MATK; MERTK; MET; MLTK; MST1R; MUSK; NPR1;NTRK1; NTRK2; NTRK3; PDGFRA;PDGFRB; PLK4; PTK2; PTK2B; PTK6; PTK7; RET; ROR1; ROR2; ROS1; RYK; SGK493; SRC; SRMS; STYK1; SYK; TEC; TEK;TEX14; TIE1; TNK1; TNK2; TNNI3K; TXK; TYK2; TYRO3; YES1; ZAP70
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023dr rahul ts
Tyrosine Kinase Types
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1. Receptor tyrosine kinases eg: EGFR, PDGFR, FGFR
2. Non-receptor tyrosine kinases eg: SRC, ABL, FAK and Janus kinase
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023dr rahul ts
Oncogenic Activation of Receptor Tyrosine Kinases
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Normally the level of cellular tyrosine kinase phosphorylation is tightly controlled by the antagonizing effect of tyrosine kinase and tyrosine phosphatases.
Protein kinases can become mutated, stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer
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Targeted Therapy
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Is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth.
Rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy).
mAbs and sTyrosine kinase inhibitors
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
May 1, 2023dr rahul ts
Characteristics Structure
mAbs TkIs
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Large (M.wt-150,000 daltons), water soluble
Do not cross cell membrane and have extracellular targets
Small (M.wt-400-500 d )
Cross cell membrane and act on intracellular targets
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Characteristics Specificity
mAbs TkIs
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Single known molecular target
Most specific drugs
May have multiple targets
Although it increase anti-tumor effects, may also increase toxicities
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Characteristics Mechanism
mAbs TkIs
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Activation or antagonize igand-receptor binding
Immune functionsAntibody
dependent celular cytotoxicity ADCC
Compliment mediated cytotoxicity CMC
Deliver radio-isotops, toxins or drugs
Completely bind substrate binding sites
Thus inhibit phosphorylation and further downstream signal transduction
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Characteristics Administration mAbs TkIs
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As protiens,Abs denatured in G.I.
i.v.Half life in days
Given weekly/monthly
Combination with cytotoxic chemo
Orally
Half life in hrsGiven o.d.
Monotherapy
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Characteristics Toxicities
mAbs TkIs
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Acute infusion reactionsWhich reflects drug
interaction with molecular targets (cytokine dependent rxns) and host immune response to the drug (hypersensitivity rxns)
Target asso. effect
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Tyrosine Kinase Inhibitor
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1. BCR-ABL Tyrosine Kinase Inhibitors
eg: Imatinib, Dasatinib, Nilotinib.
2. Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors eg: Gefitinib, Lapatinib.
3. Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors
eg: Semaxinib, Vandalinib, Sunitinib, Sorafenib.
Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy
Tyrosine Kinase Inhibitor
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Currently, 12 mAbs and 15 TkIs are FDA-approved for the treatment of cancer
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Name Targets Indications ToxicitiesBortezomib (velcade)
26 s proteosome
Multiple myeloma, mantle cell lymphoma
peripheral neuropathy, rash, diarrhea, edem, nausea
Crizotinib (xalkori)
ALK, MET ALK +ve NSCLCa GIT, hepatic, renal, pulmonary, visual
Lapatinib(tykerb)
HER2, EGFR
Breast Ca with HER2 overexpression
Cardiac, rash, H-F syndrome, diarrhea, hepatic
Erlotinib (tarceva)
EGFR NSCLCa, pancreatic cancer
rash, diarrhea, nausea, hepatic, pulmonary, conjuctivitis
Geftinib (iressa)
EGFR NSCLCa rash, diarrhea, hepatic, pulmonary
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Name Targets Indications
Toxicities
Imatinib (gleevac)
BCR-ABL, c-KIT, PDGFR
CML, ALL,GIST, mastocytosis, hyperesinophillic syndrome.
Rash, edem, nausea, wt.gain, pleural effusion, Cardiac, arthralgia and myalgia.
Dasatinib(sprycel)
BCR-ABL, SRC family, c-KIT, PDGFR
CML, ALL Rash, edem, pleural effusion, QT prolongation, mucositis.
Nilotinib (tasigna)
BCR-ABL, c-KIT, PDGFR
CML Rash, edem, nausea, arthralgia and myalgia
Pazopanib (votrient)
VEGFR, PDGFR, FGFR
RCC Hypertension, hair colour changes, nausea, hepatic,
Sorafinib(nexavar)
BRAF, VEGFR, EGFR, PDGFR
RCC, HCC Hypertension, alpacia, rash, HF syndrome, wound healing complication, elevated lypase and amylase,hypophosphatemia
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Name Targets Indications
Toxicities
Sunitinib (sutent)
VEGFR, PDGFR, c-KIT, FLT3
RCC, GIST Nausea, yellow discoloration of skin,thyroid, cardiac, adrenal,hepatic, renal, mucositis, diarrhea
Temserolimus (torisel)
mTOR RCC Rash, edema, increased glucose, dyslipidemia, hepatic, renal
Everolimus (affinitor)
mTOR RCC Rash, edema, increased glucose, dyslipidemia, hepatic, renal
Vemurafinib(zelboraf)
BRAF Melanoma Alpecia, dermatologic, GI, arthralgia, skin papillomas
Vandetanib(caprelsa)
EGFR,VEGFR
Medullary thyroid carcinoma
Dermatologic, QT prolongation, GI, HTN
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