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FAK INHIBITORS: A STRATEGY TO COMBAT CANCER
BY MADHURI H.JAIN F.Y.M-PHARM(PHARM.CHEM.)
UNDER THE GUIDANCE OF Dr. RAKESH R. SOMANI
(HOD:PHARMACEUTICAL CHEMISTRY)
Thursday 13 April 2023
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CONTENTS
Cancer Rationale for FAK inhibition Introduction to FAK Basic activation pathways of FAK FAK inhibitors Clinical Challenges Conclusion
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CANCER Cancer is characterized by unregulated and
uncontrolled growth of cells. Normal cells undergo a programmed cell death (apoptosis).
However, cancer cells do not undergo apoptosis, and continue to grow and divide forming malignant (cancerous) tumors.
If the spread of these tumors to the other organs of the body is not controlled, it can result in death.
To prevent the unregulated and uncontrolled growth of cells, many anti-cancer agents have been developed.
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TYPES OF AGENTS MECHANISM OF ACTION EXAMPLES
ALKYLATING AGENTS AND ANTIBIOTICS
INHIBIT DNA SYNTHESIS AND CELL DIVISION
CYCLOPHOSPHAMIDE, DACTINOMYCIN
ANTIMETABOLITES
FOLATE ANTAGONIST INHIBITS DHFR METHOTREXATEPURINE ANTAGONIST INHIBITION OF PURINE
RING BIOSYNTHESISMERCAPTOPURINE
PYRIMIDINE ANTAGONIST INHIBITION OF PYRIMIDINE RING BIOSYNTHESIS
FLUOROURACIL
NATURAL COMPOUNDS
VINCA ALKALOIDS INHIBITION OF TUBULIN VINCRISTINE
HORMONAL ANTAGONIST
AROMATASE INHIBITORS INHIBITION OF AROMATASE
ANASTRAZOLE
ANTI-ANDROGEN AGENT INHIBITION OF ANDROGEN RECEPTOR
FLUTAMIDE
LIST OF ANTICANCER AGENTS
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DISADVANTAGES OF CONVENTIONAL THERAPIES
However, the conventional therapies are associated with problems such as:Severe toxicityDevelopment of resistance Not well tolerated in patientsNot cell specificRelapse of cancer
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RATIONALE FOR FAK INHIBITION: FAK is a key regulator of cell survival, proliferation,
migration and invasion: processes that are all involved in the development and progression of cancer.
FAK is also linked to oncogenes at both biochemical and functional level.
Overexpression of FAK in wide variety of cancer is quite significant.
Important role of FAK in tumorigenesis, angiogenesis, metastasis and survival signalling FAK should be regarded as a potential target in the development of anti-cancer drugs.
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INTRODUCTION TO FOCAL ADHESION KINASE (FAK)
Focal adhesion kinase (FAK) is a 125- kDa non receptor, cytoplasmic tyrosine kinase that modulates cell adhesion, migration, proliferation and survival of cell.
It belongs to protein tyrosine kinase family. In addition to being a key player in regulating normal
cellular activities such as adhesion, migration and survival, FAK is also implicated in cancer cell invasion, metastasis and survival.
FAK is linked to the protection of cells from anoikis (suspension induced cell death).
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FAK STRUCTURE: It is encoded by a gene located on chromosome 8 in human
and houses three domains, the amino-N-terminal domain, the central catalytic domain and the carboxyl-C-terminal domain.
SCHEMATIC DIAGRAM OF FAK DOMAIN STRUCTURE WITH PHOSPHORYLATION SITES
FIGURE NO1
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FUNCTIONS OF FAK:
ROLE OF FAK
ANGIOGENESIS
CELL ADHESION AND MIGRATION
CELL INVASION
CELL PROLIFERATION AND SURVIVAL
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CONTINUED…
FAK is activated through phosphorylation of its tyrosine sites like Tyr-397,407,576,577,861,925.
It is achieved through various pathways like:Src –FAK pathwayVEGFR-FAK pathwayPDGFR-FAK pathway
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BASIC ACTIVATION PATHWAY OF FAK:
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SRC-FAK PATHWAY:
FAK has a autophosphorylation site which is Tyr397. It act as a binding site for SH2 domain of Src to the
FAK. This FAK-Src complex promotes phosphorylation of
other tyrosine sites like Tyr-407,576,577,861and 925 leading to increased activity of FAK.
Thus promoting cell growth, cell adhesion and its survival.
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SRC-FAK PATHWAY:
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VEGFR-FAK PATHWAY
VEGF RELEASED FROM CELLS EXPOSED TO
HYPOXIA
VEGF BINDS TO VEGFR
CAUSES DIMERIZATION OF
RECEPTOR
LEADS TO PHOSPHORYLATION
OF FAK ENZYME
FAK ACTIVATION THROUGH VEGFR
LEADS TO ANGIOGENESIS
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VEGFR-FAK PATHWAY:
VEGF (VASCULAR ENDOTHELIAL GROWTH FACTOR) is a proangiogenic factor.
VEGF is released from cells which are exposed to hypoxia and partly because of increased transcription.
Binding of VEGF takes place to vascular endothelial growth factor receptor(VEGFR).
This leads to dimerization of the receptor. This cause phosphorylation of FAK. FAK activation through VEGF leads to angiogenesis, thus
providing continuous blood supply to cancerous cell.
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PDGFR-FAK PATHWAYPDGF RELEASED FROM MALIGNANT AND INFLAMMED CELLS
PDGF BINDS TO PDGFR
DIMERIZATION OF RECEPTOR TAKES PLACE
PHOSPHORYLATION OF SER-910 SITE OF FAK
ACTIVATION OF ENDOTHELIAL CELLS TO SECREATE MATRIX METTALOPROTEASES
THUS CAUSING MIGRATION AND PROLIFERATION
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PDGFR-FAK PAYTHWAY PDGF(PLATELET DERIVED GROWTH FACTOR) It is also a type of proangiogenic actor. It is released into the microenvironment by malignant, inflammatory and other
stromatal cells in response to various stimuli. PDGF binds to PDGF RECEPTOR which causes dimerization of receptor. This causes phosphorylation of Ser-910 site of FAK. This leads to activation of endothelial cells, stromatal cells and circulating endothelial
progenitor cells(CEPs) secrete several enzymes including matrix metalloproteases (MMPs) that break down the extra cellular matrix and allows endothelial cells to invade surrounding tissue thus causing proliferation and migration of cells.
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FAK INHIBITORS:
FAK inhibitors can be divided into two main groups: The first group includes inhibitors targeting enzymatic
or kinase-dependent functions of FAK, such as inhibitors targeting the ATP-binding site domain and allosteric inhibitors that target other sites of FAK yet still block kinase activity, and
The second group includes inhibitors that target the FAK pathway.
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MECHANISM OF ACTION:(DRUGS TARGETING ATP BINDING SITE
For drugs like TAE-226 , PF-573,228 , PF-562,271 PND-1186 , COMPOUND 14
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TAE-226: Targets ATP binding site Y-397 on
FAK enzyme
PF-573,228 : blocked catalytic activity of recombinant FAK
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PF-562,271:Inhibits the phosphorylation of Tyr-397
PND-1186Inhibits FAK kinase activity , targets FAK binding site
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NOVEL ALLOSTERIC FAK INHIBITORS:
Takeda developed non-ATP-competitive FAK allosteric inhibitors that efficiently decreased FAK functions. The Takeda identified tricyclic sulfonamides (compounds 1 and 2) that targeted a novel allosteric site in the C-lobe of the kinase domain, caused conformational changes of the kinase domain and induced disruption of ATP pocket formation and inhibition of FAK kinase activity
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MECHANISM OF ACTION :(DRUGS TARGETTING ALLOSTERIC SITE)
For drugs like Compound 1&2.
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INHIBITS BY BINDING TO ALLOSTERIC SITE OF THE FAK
INHIBITS BY BINDING TO ALLOSTERIC SITE OF THE FAK
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DRUGS TARGETING FAK PATHWAY:
Since FAK has so many binding partners such as Src, VEGFR,PDGF disruption of these complexes is an additional therapeutic approach to disrupt signals that FAK integrates and effectively block FAK regulated functions, another approach is to disrupt FAK interaction with these proteins.
The first approach to target the of FAK was performed by disrupting FAK and VEGFR with C4
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C4
Targets FAK-VEGFR pathway interaction.
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MISCELLANEOUS INHIBITORSA) Antisense oligonucleotides : They are single stranded DNA or RNA that are
complementary to a chosen sequence. They are directed towards the 5’ mRNA sequence of
FAK. When combined with 5-fluorouracil leads to
decreased FAK expression. Used in melanoma
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Antisense oligonucleotides:
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B) Thioridazine : It is an antipsychotic and anti anxiety drug. But has shown antiangiogenesis effect by inhibiting
phosphorylation of FAK, inhibiting VEGFR-FAK pathway.
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C) Mitoxantrone : It is type 2 topoisomerase inhibitor It has shown FAK inhibition by targeting ATP binding site. It acts on Src as well.
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CLINICAL CHALLENGES
Sensitivity of tumor cells to FAK Inhibitors Specificity of FAK inhibitors Discovery of biomarkers Single use or combination Chemoresistance
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CONCLUSIONo FAK research has answered many questions about
FAK-binding partners, the structure of its major domains and mechanisms of survival signalling. However, there are many questions that still remain unanswered about FAK to be answered in the future.
o Given the central role of FAK in cancer functions further refinements and understanding of its signalling pathways will lead to novel cancer therapy approaches.
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ACKNOWLEDGEMENT:
Dr. Rakesh R. SomaniDr .Supriya ShidhayeTeaching and non-teaching staffMy seniorsFamily and friends
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THANK YOU
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REFERENCES G.W. McLean, N.O. Carragher, E. Avizienyte, J. Evans, V.G. Brunton, M.C.
Frame,The role of focal-adhesion kinase in cancer - a new therapeutic opportunity , Nature Review Cancer 5 (2005) 505-515.
J.K. Slack-Davis, K.H. Martin, R.W. Tilghman, M.Iwanicki, E.J. Ung, C. Autry,M.J. Luzzio, B. Cooper, J.C. Kath, W.G. Roberts, J.T. Parsons, Cellular characterization of a novel focal adhesion kinase inhibitor, J. Biol. Chem. 282 (2007) 14845-14852.
Carragher, N. O. & Frame, M. C. Focal adhesion and actin dynamics: a place where kinases and proteases meet to promote invasion. Trends Cell Biol.(2004) 14,241-249.
Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther.(2005);315(3):971–9.
W.G. Cance, J.E. Harris, M.V. Iacocca, E. Roche, X. Yang, J. Chang, S. Simkins,L. Xu, Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes, Clin. Cancer Res. 6 (2000) 2417-2423.
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REFERENCES: D. Lietha, M.J. Eck, Crystal structures of the FAK kinase in complex with
TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation, PLoS One 3 (2008) 3800.
A. Schultze, W. Fiedler, Clinical importance and potential use of small molecule inhibitors of focal adhesion kinase, Anti-Cancer Agents in Medicinal Chemistry 11 (2011) 593-599.
S.T. Arold, M.K. Hoellerer, M.E. Noble, The structural basis of localization and signaling by the focal adhesion targeting domain, Structure 10 (2002) 319-327.
Choi, H.-S.; Wang, Z.; Richmond, W.; He, X.; Yang,K.;Jiang, T.; Sim, T.; Karanewsky, D.; Gu, X.-J.; Zhou, V.;Liu, Y.; Ohmori, O.; Caldwell, J.; Gray, N.; He, Y. Bioorg.Med. Chem. Lett. 2006.
Golubovskaya VM, Virnig C and Cance WG: TAE226-inducedapoptosis in breast cancer cells with overexpressed Src or EGFR. Mol Carcinog 47: 222-234,2008