May 1, 20231

TYROSINE KINASE INHIBITORS

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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.

dr rahul ts

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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