Med Chem of Tyrosine Kinase Inhibitors (Dr. Parang)

Which type of kinase inhibitors bind to the active conformation of the kinase and compete with ATP?

Type 1 inhibitors

Type 2 inhibitors

Type 3 inhibitors

Type 4 inhibitors

1

Which one of these kinases is a non-receptor kinase?

1. JAK

2. EGFR

3. VEGFR

4. PDGFR

1

What is the mechanism of resistance for Imatinib?

A. The point mutation of a gatekeeper amino acid

B. Slow metabolism

C. Rapid metabolism by CyP450

D. Binding to P-gp

A

What is the gatekeeper residue in Bcr-Abl kinase that affects the binding of certain inhibitors?

A. Aspartate

B. Methionine

C. Threonine

D. Isoleucine

C

matinib and nilotinib are examples of which type of Bcr-Abl inhibitors?

A. Type 1

B. Type 2

C. Type 3

D. Type 4

B

Which of the following drugs have 2-phenylaminopyrimidine as a pharmacophore?

A. Sorafenib

B. Dasatinib

C. Erlotinib

D. Lapatinib

E. Nilotinib

E

Which Bcr_Abl inhibitor exhibits potent T315I inhibitory activity and was developed to overcome steric hindrance in the binding pocket?

A. Nilotinib

B. Imatinib

C. Ponatinib

D. Dasatinib

C

Which of the following receptor tyrosine kinases (RTKs) belongs to the HER family?

A. FGFR

B. IGFR

C. EGFR

D. MET

C

Which HER kinase is also known as ErbB1 and is commonly targeted in cancer therapy?

A. HER2

B. HER3

C. HER4

D. EGFR

D

Which of the following is an example of a Type 1 inhibitor? Select all that apply.

A. Gefitinib

B. Imatinib

C. Nilotinib

D. Erloitinib

A,D

Which one of these inhibitors has 4-anilinoquinazoline pharmacophore? Select all that apply.

A. Erlotinib

B. Sorafenib

C. Gefitinib

D. Ruxolitinib

A,C

What is angiogenesis?

A. Formation of new blood vessels from the endothelium of existing vessels.

B. The death of blood vessels from the endothelium of existing vessels.

C. The fusion of blood vessels from the endothelium of existing vessels.

D. The remodeling of blood vessels from the endothelium of existing vessels.

A

Which of the following is a key enzymatic player in the generation of new blood vessels?

A. VEGF1

B. VEGF2

C. VEGF3

D. VEGF4

B

Which of the following is a type 2 TKI?

A. Sorafenib

B. Sunitinib

C. Gefitinib

D. Erlotinib

A

Which of the following compounds targets both inactive and active conformation of tyrosine kinase? (Select all that apply)

A.Sunitinib

B. Dasatinib

C. Erlotinib

D Gefitinib

E. Sorafenib

A,B

two types of Tyrosine kinases are

• receptor associated

• cytoplasmic (nonreceptor)

example of receptor tyrosine kinases

EGFR, VEGFR

non receptor tyrosine kinase receptors examples

JAK, BCR-ABL, RAS

type 1 inhibitors bind to what conformation

active

type 2 inhibitors inhibit what conformation

inactive

examples of type 1 inhibitors

gefitinib

erlotinib

type 2 inhibitors drugs

imatinib

nilotinib

sorafenib

vatalanib

binds to the active conformation of kinase with aspartate residue is what type of

type 1 inhibitors

bind and stabilize the inactive conformation of the kinase with the flipped aspartate is what type

type 2 inhibitors

occupy an allosteric pocket that is adjacent to ATP binding pocket but no overlap is what inhibitor

type 3 inhibitors

bind to allosteric pocket remote from ATP binding pocket is what type

type 4 inhibitors

which type contain a heteroaromatic ring

type 1 inhibitors

which targets are nonreactor kinases

BCR-Abl

RAS

JAK

what is a RAS inhibitor drug for advanced solid tumors

daraxonrasib

diagnosis of CML is usually confirmed by detection of what

philadelphia chromosome

what are the Philadelphia choromose

9 and 22

bind to both ATP hinge region and to adjacent hydrophobic subdomains of BCR-Abl (t/f)

true

• thr to lle mutation at position 315

• residue 315 known as gatekeeper to hydrophobic binding pocket

• more significant bulk of lle residue block imatinib access

resistance of imatinib

which BCR-ABL inhibitor can inhibit T3151

ponatinib

contains 2-phenylaminopyrimidine pharmacophore

imatinib and nilotinib

what are conferred by the substituted piperazine and imidazole

imatinib and nilotinib

exhibits potent T315l inhibitory activity is what drug

ponatinib

mixed type 1 and type 2 BCR-Abl kinase inhibitors

dasatinib

• both the active and inactive conformations

• effective against all imatinib resistant mutants except T315l, does not bind to P-gp

dasatinib resistance

contraindicated PPI with what class ?

nilotinib, dasatinib, bosutinib, and ponatinib

what are the examples of epidermal growth factor receptors?

EGFR

ErbB-1

HER-1

EGFR and HER2 are closely related membrane bound TKs (t/f)

true

treatment resistance breast, ovarian, lung, and gastric cancer is what over expression

HER2

contains 4-anilinoquinazoline pharmacophore is what inhibitors

EGFR inhibitors

erlotinib and geftiqiv are what type of TKIs

type 1 TKIs

entire substituted aniline structural component of lapatinib binds within a lipophilic pocket of HER2 kinase in its active conformation is what drug

lapatinib

important signaling protein involved in both vasculogenesis and angiogenesis

VEGF

what is a key enzymatic player in the generation of new blood vessels

VEGF2

which binds to VEGFR in its inactive conformation (type 2 inhibitors)

sorafenib

life threatening DDI involved kinase inhibitors

antibiotics, antifungals, HIV, certain antidepressants

which class is a serine/threonine kinase

BRAF

All BRAF inhibitors are type 1 inhibitors targeting active BRAF conformation (t/f)

true

• bind active kinase, overlap DFG motif is SAR of what

BRAF