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

a. type 1 inhibitors

b. type 2 inhibitors

c. type 3 inhibitors

d. type 4 inhibitors

a. type 1 inhibitors

which one of these kinases is a non-receptor kianse?

a. JAK

b. EGFR

c. VEGFR

d. PDGFR

a. JAK

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. the point mutation of a gatekeeper amino acid

What is the gatekeeper residue in Bcrl-Abl kinase that affects the binding of certain receptors?

a. aspartate

b. methioinine

c. threonine

d. isoleucine

c. threonine

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

a. type 1

b. type 2

c. type 3

d. type 4

b. type 2 (inactive)

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

a. sorafenib

b. dasatinib

c. erlotinib

d. lapatinib

e. nilotinib

e. nilotinib

which Bcr-Abl inhibitor exhibits potent T315I activity and was developed to overcome steric hinderance in the binding pocket?

a. nilotinib

b. imatiniib

c. ponatinib

d. dasatinib

c. ponatinib

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

a. FGFR

b. IGFR

c. EGFR

d. MET

c. EGFR

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

a. HER2

b. HER3

c. HER4

d. EGFR

d. EGFR

which HER kinase lacks intrinsic tyrosine kinase acitivty?

a. HER2

b. HER3

c. HER4

d. EGFR

b. HER3

which of the following is an example of a type 1 inhibitor? select all that apply

a. gefitinib

b. imatinib

c. nilotinib

d. erlotinib

a. gefitinib

e. erlotinib

which one of these inhibitors has 4-anilinoquinazoline pharmacophore? select all that apply

a. erlotinib

b. sorafenib

c. gefitinib

d. ruxolitinib

a. erlotinib

c. gefitinib

what is angiogenesis?

a. formation of new blood vessels form 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. formation of new blood vessels form the endothelium of existing vessels

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. VEGF2

which of the following is a type 2 TKI?

a. sorafenib

b. sunitinib

c. gefitinib

d. erlotinib

a. sorafenib

which of the following compounds target both inactive and active conformation of tyrosine kinase (select all that apply)

a. sunitinib

b. dasatinib

c. erlotinib

d. gefitinib

e. sorafenib

a. sunitinib

b. dasatinib

what are potential DDIs for camptothecin analogs?

topotecan and irinotecan are metabolized by CYP3A4

• azole antifungal agents —> reduces camptothecin clearance (↑ concentration)

• phenobarbital and phenytoin (CYP3A4 inducers) —> accelerated clearance (↓ concentration)

how to reduce hypersenitivity resulting from etoposide formulations?

epinephrine, antihistamines, and corticosteroids

• etoposide formulated with polysorbate 80 (tween)

• teniposide formulated with polyoxyethylated castor oil (Cremphor EL)

what do you recommend to reduce cardiotoxicity of doxorubicin

dexarazoxane

onivyde

a pegylated liposomal formulation of irinotecan

• Stable in the circulation, and is preferentially taken up and retained for a longer
  period of time in the tumor cell.

• The elimination t1/2 of liposomal irinotecan and SN-38 is approximately 26 and
  68 hours, respectively. SN38 is detectable in plasma for up to one week (slower
  clearance).

• Binding to serum proteins is blocked by the polyethylene glycol attached to the
  liposomal surface.

• The inclusion of PEG chains decreases phagocytosis by tissue
  macrophages.

• The size (110 nm) aids in accumulating in tumor tissues.

• SN38 has a lower maximum concentration (Cmax) than free Irinotecan.

• A more potent therapeutic effect with fewer adverse reactions: The boxed
  warning for life-threatening neutropenia and diarrhea still applies.

• Indicated for the treatment of the metastatic pancreas.

anthracycline cardiotoxicity

• these cytotoxic radicals are generated within the heart, however, and can lead to acute reversible cardiotoxicity

• when hydrogen peroxide forms in the myocardium, it has no choice but to go down the Fenton pathway and iron accumulation

• coadministration of dexrazoxane (an antioxidant and iron chelator) has been shown to lower its incidence

Doxil

PEGylated liposomal doxorubicin

• reduced cardiotoxicity

• prolonged circulation time

• improving tumor uptake through the EPR effect

why do kinase inhibitors acquire resistance? What strategy can be used to circumvent resistance?

• Resistance mechanisms are often associated with point mutations in the Abl (kinase)
  domain, in particular a threonine (Thr) to Ile mutation at position 315 (T315I).

• Residue 315 is known as the “gatekeeper” to the hydrophobic binding pocket

• The more significant bulk of the Ile residue blocks imatinib’s access to this receptor through steric interference with the benzyl moiety.

• Sixteen percent of all Bcr-Abl mutations are T315I, and CML patients carrying this mutation have a poor prognosis.

• Panotinib exhibits potent T315I inhibitory activity

dasatinib

• Because it can bind to both the active and inactive conformations of Bcr-Abl kinase, dasatinib has a potency approximately 325 times that of imatinib, and it can be used in patients resistant to imatinib or nilotinib.

• Most mutations that confer resistance to imatinib occur in the P-loop of the kinase, an area not important to dasatinib binding.

• Dasatinib is effective against all imatinib-resistant mutants except T315I, and does not bind to P-gp

what are the major DDIs for kinase inhibitors?

• CYP3A4 metabolizes the greatest number of clinically relevant drugs

• Inhibition of CYP3A4 can lead to increased levels of the kinase inhibitor, potentially causing toxicity, while induction of CYP3A4 can decrease the levels, reducing the efficacy of the kinase inhibitor.

• Examples of medications that can interact with CYP3A4 include certain antibiotics, antifungals, HIV protease inhibitors, and certain antidepressants.

• Dosing adjustments are required if coadministration cannot be avoided

why coadministration of antacids, H₂ antagonists, and PPIs must be avoided for some tyrosine kinase inhibitors?

• Nilotinib and dasatinib, bosutinib, ponatinib absorption require gastric acidity (pH ≤3.7)

• Contraindication with drugs that raise gastric pH (e.g. proton pump inhibitors, H2 antagonists)

• Coadministration with these TKIs should be separated by at least two hours or avoided
  altogether