1.5 Targeted therapies

bolinger

primary MOA of targeted therapy in cancer tx

blocking specific molecular targets involved in tumor growth

VEGF-B binds to which receptor(s)

VEGFR-1

VEGF-A binds to which receptor(s)

VEGFR-1 and 2

VEGF-E binds to which receptor(s)

VEGFR-2

VEGF-C binds to which receptor(s)

VEGFR-2 and 3

VEGF-D binds to which receptor(s)

VEGFR-2 and 3

which veggies bind to VEGFR-1? select all that apply

a. VEGF-A

b. VEGF-B

c. VEGF-C

d. VEGF-D

e. VEGF-E

a and b

which veggies bind to VEGFR-2? select all that apply

a. VEGF-A

b. VEGF-B

c. VEGF-C

d. VEGF-D

e. VEGF-E

a, c, and e

which veggies bind to VEGFR-3? select all that apply

a. VEGF-A

b. VEGF-B

c. VEGF-C

d. VEGF-D

e. VEGF-E

c and d

what is the most pursued target for cancer therapy

tyrosine kinases

kinase structure:

what are the 5 main parts

N-terminal lobe

ATP binding pocket

hinge

activation loop

C-terminal lobe

kinases catalyze terminal phosphate groups of ATP to substrates that contain which amino acids (3)

Ser, Thr, or Tyr

kinases bind to the ___ of ATP and extend to the substrate binding site

hydrophilic channel

activation loops of kinases can ____ substrate binding sites

open or block

drugs that mimic ATP are able to inhibit _____ on kinases

ATP binding sites

drugs that mimic ATP have ____ interactions with amino acids in the hinge region of kinases

1-3 H bond

type 1 inhibitors are ATP _____ and they bind to active kinase conformation

competitive

type 1 inhibitors are ATP competitive, they mimic the ____ that is in the purine binding site hydrophobic pocket

heterocyclic ring system

type II inhibitors:

recognize ____ kinases DFG-Out conformation

inactive

which type of kinase inhibitor works on active kinases?

type I

which type of kinase inhibitor works on inactive kinases?

type II

type II inhibitors: the movement of the activation loop exposes _____ directly adjacent to the ATP binding site

additional hydrophobic binding site

type II inhibitors: the movement of the activation loop exposes additional hydrophobic binding site directly adjacent to ____

the ATP binding site

all kinase inhibitors have which structural components?

allosteric site

2 hydrophobic pockets

imatinib mesylate class

Bcr-ABL kinase inhibitor

nilotinib HCl class

Bcr-ABL kinase inhibitor

dasatinib class

Bcr-ABL kinase inhibitor

gefitinib class

1st generation EGFR TKI

erlotinib

1st generation EGFR TKI

dacomitinib class

2nd generation EGFR TKI

afatinib class

2nd generation EGFR TKI

osimertinib class

3rd generation EGFR TKI

rociletinib class

3rd generation EGFR TKI

brigatinib class

4th generation EGFR TKI

erlotinib is a ______ TKI

a. reversible

b. irreversible

b

erlotinib acts on which receptor?

epidermal growth factor receptor (EGFR)

where does erlotinib bind on EGFR

ATP binding site

what reaction occurs for erlotinib binding to EGFR

H bond with Met769

erlotinib metabolism occurs in which organ

liver

which enzyme metabolizes erlotinib

CYP3A4

CYP3A4 activator examples

rifampicin

st johns wort

CYP3A4 activators (rifampicin and st johns wort) can _____ conc of erlotinib

lower

erlotinib metabolism:

what two rxns does CYP3A4 do

O-dealkylation and aromatic hydroxylation

erlotinib metabolism:

O-dealkylation metabolite is further metabolized by what enzymes

alcohol dehydrogenase and aldehyde dehydrogenase

erlotinib metabolism:

the aromatic hydroxylation metabolite is further metabolized to form…

hepatotoxic quinoneimine

gefitinib metabolism:

what rxn does CYP2D6 cause

dealkylation

gefitinib metabolism:

what reactions metabolize it

dealkylation, defluorination, hydroxylation

gefitinib metabolism:

the ____ product can be further metabolized to form a hepatotoxic quinoeimine

defluorination, hydroxylation

gefitinib metabolism:

the defluorination, hydroxylation product can be further metabolized to form _____

hepatotoxic quinoeimine

gefitinib contains which important structure

morpholine ring

most TKIs develop resistance w/n ___ yrs of use

2-5

most resistance to TKIs result from…

EGFR mutation

second generation TKIs bind ______

a. reversibly

b. irreversibly

b

second generation TKIs are ____ derivatives

quinazoline

second generation TKIs covalently bind with _____ at the ATP binding pocket

cysteine residues

Afatinib MOA

Dual EGFR & HER-2 kinase inhibitor.

Afatinib binds ____ to the ATP binding site via Cys

irreversibly

Afatinib binds irreversibly to the ATP binding site via___-

Cys

Afatinib is a ____ derivative

4-anilinoquinazoline

Afatinib is in the form of a ____

di-maleate salt

Afatinib has a H bond interaction between the ____ and the hinge region of the quinazoline

amide N of Met793

Afatinib has a H bond interaction between the amide N of Met793 and the ______

hinge region of the quinazoline

Osimertinib is given via…

a. IV

b. oral

c. subq

b

Osimertinib binds ____ to EGFR

a. reversibly

b. irreversibly

b

Osimertinib binds to EGFR proteins with a ______

T790M mutation

Osimertinib binds irreversibly to EGR with which mutations?

T790 M

L858R

exon 19 deletion

Brigatinib targets the ____ mutation of EGFR

T790M

Brigatinib avoids inhibition of ____

native EGFR

Brigatinib acts on ____ and mutated EGFR

anaplastic lymphoma kinase (ALK)

Brigatinib can overcome triple mutant EGFR if it is combined with…

an antiEGFR antibody

Alemtuzumab class

monoclonal antibody

Alemtuzumab binds to ___ on the surface of mature lymphocytes

CD52

Alemtuzumab binds to CD52 on ______

the surface of mature lymphocytes

How do EGFR inhibitors reduce tumor growth?

By blocking receptor activation → preventing downstream signaling through MAPK and PI3K/AKT pathways

What happens if EGFR signaling is constitutively active

Uncontrolled proliferation + resistance to apoptosis

antibodies can be directed against ___ to inhibit signaling for cell growth

extracellular domain

EGFR exists in ___ conformations

open and closed

Bevacizumab MOA

inhibits VEGF-A

VEGF-A signals stimulate ____ in many dx

angiogenesis

Trastuzumab MOA

interferes with the HER2/neu receptor

Pertuzumab binds to ____

HER2 extracellular domain

Vemurafenib MOA

BRAF inhibitor

Immunization with ___________ or both can stimulate patient’s own immune system to develop specific high-affinity antibodies

antigenic peptides containing B- or T-cell epitopes

Pembrolizumab class

PD-1-PDL1 inhibitor

Pembrolizumab MOA

replicates in tumors to make GMCSF

Thalidomide:

what is the active form

R

Thalidomide has both ____ and ______ activity

immunosuppressive and anti-angiogenic

Thalidomide MOA:

inhibits release of tumor necrosis factor-alpha (TNF-α) from monocytes, and modulates other cytokines

Thalidomide solubility

poor

Thalidomide metabolism

non-enzymatic hydrolysis in plasma by CYP450

Thalidomide end product

phthalic acid excreted as a glycine conjugate

Lenalidomide is a derivative of ____

thalidomide

which is more potent?

a. thalidomide

b. Lenalidomide

b

Lenalidomide MOA

inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis

Lenalidomide absorption

rapidly after oral admin

Lenalidomide metabolism

unchanged

Pomalidomide is an analog of ______

thalidomide

Pomalidomide has both ____ and ______ effects

immunomodulatory & antineoplastic

which is the most potent?

a. lenalidomide

b. thalidomide

c. pomalidomide

c

Pomalidomide metabolism is by which enzymes

CYP1A2 and CYP3A4.