Anticancer- Kinase Inhibitors

most common mutation in cancers

TP53

what drives kinase signaling and what is the major source

transfer of phosphates, ATP

types of kinases

tyrosine, serine, threonine

what balances the activity of kinases by removing phosphates

phosphatases

structure of kinases

N- and C- lobes connected by a hinge region with an activation loop inside the hinge region

type I kinase inhibitor

Bind to the ATP pocket of the active conformation

type II kinase inhibitor

binds and stabilizes the inactive conformation of the kinase

type III kinase inhibitors

occupy an allosteric pocket outside of the ATP-binding pocket

how do competitive inhibitors work

bind in a reversible fashion and must compete with ATP for binding

how do covalent inhibitors work

covalently bind with a reactive nucleophilic cysteine leading to irreversible inhibition in the ATP site

how does EGFR function and what happens when it is mutated

through tyrosine kinase activity, mutations lead to constitutive activity inducing cell proliferation

first generation EGFR inhibitors

gefitinib and erlotinib

ways cancers form resistance

mutations in the protein (EGFR) that prevent drug binding

activation of alternative pathways

activation of downstream effectors

histological transformation

what mutation in EGFR causes resistance to gefitinib

T790M

2nd + 3rd generation EGFR inhibitors that can overcome T790M mutation and how they work

afatinib and osimertinib- covalently inhibit the EGFR tyrosine kinase by binding to cystein 797

what protein is mutated in breast cancer

HER2

small molecule TK inhibitor that blocks HER2 and EGFR signaling

lapatinib (tykerb)

what is lapatinib combined with and what does this combination treat

combined with capecitabine for treatment of advanced metastatic breast cancer caused by HER2 who have progressed from other therapies

first line anti HER2 treatment

trastuzumab + pertuzumab

which EGFR inhibitor is best at overcoming the T790M mutation

osimertinib

FLT3 mutations lead to what cancer

acute myeloid leukemia

what are the two FLT3 mutations and which is more common

internal tandem duplication (ITD- more common) or activating mutation in the tyrosine kinase domain (less common)

role of FLT3 ligand

hematopoietic cell survival and proliferation

first generation FLT3 inhibitor

midostaurin

second generation FLT3 inhibitor

crenolanib (more specific)

type II FLT3 inhibitor and what its specific for

quizartinib (ITD mutations)

chromosomal translocation that produces Bcr-Abl and is responsible for chronic myeloid leukemia

philadelphia chromosome (Ph1)

what pathways are driven by Bcr-Abl

MAPK, PI3K, JAK/STAT

what type of kinase is the Abl protein

tyrosine kinase

what is caused by the Bcr-Abl chimeric protein and why

malignancy because it is constitutively active

what inhibitory activity does Bcr-Abl have

against other tyrosine kinases such as PDGFR and c-Kit

used to treat chronic myelocytic leukemia (CML) patients that have the Bcr-Abl translocation

imatinib

what type of inhibitor is imatinib

type II small molecule inhibitor of the Abl tyrosine kinase

indication of imatinib

treatment of chronic myeloid leukemia (CML)

battle with Abl inhibitors

patients need to be on them for life so resistance is an ongoing battle

BCR-Abl inhibitor effective against all the major mutant forms of BCR-Abl

ponatinib

what is the special mutation that ponatinib can inhibit that is resistant to all other BCR-Abl compounds

gatekeeper mutation T315I

what kinase is important for normal B cell activity and B cell tumor growth

brutons tyrosine kinase (BTK)

covalent inhibitor of BTK

ibrutinib

what is ibrutinib used for

mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)

second generation covalent BTK inhibitor

acalabrutinib

indication of acalabrutinib

B cell lymphoma (MCL and CLL)

important regulator of kinase signaling

KRAS

indicated for the treatment of KRAS mutations

adagrasib, sotorasib

what mutation is treated by KRAS inhibitors and what cancer is this often found in

G12C mutations, lung cancer

how do KRAS inhibitors work

covalent inhibitors of KRAS that stabilize G12C OFF state leading to decreased signaling through MAPK and PI3K signaling

a small molecule that glues two different proteins together

daraxonrasib

how does daraxonrasib work

forces interaction of cyclophilinA with RAS(ON) which disrupts assembly of signaling pathways

problem with daraxonrasib

inhibits ALL versions of KRAS including wild type

selective inhibitor for mutant B-RAF

dabrafenib

what is the mutation of B-RAF treated by dabrafenib and what cancer is it seen in

V600E mutant, melanoma

what is B-RAF

a serine/threonine kinase in the MAPK signaling pathway

issue with dabrafenib

stimulates normal B-RAF and promotes tumor growth in melanomas with wild type enzyme

what is dabrafenib combined with for treatment of V600E/K mutant metastatic melanoma and what does this help with

trametinib, NSCLC patients

what type of cancer with BRAF mutations does not respond to dabrafetinib

colorectal cancer

another BRAF inhibitor

encorafenib and vemurafinib

MEK inhibitors and how they work

cobimetinib, trametinib, binimetinib

inhibits the kinase activity of MEK1 and MEK2

what are MEK inhibitors combined with

dabrafenib

first approved type III allosteric inhibitor of MEK1 and MEK2

trametinib

limitation of use of trametinib

not indicated for treatment of patients who have received prior BRAF inhibitor therapy

compounds that inhibit the function of mTOR (downstream pathway)

rapamycin analogues, sirolimus

what type of kinase is mTOR

serine-threonine kinase

what else does sirolimus do

inhibits immune response by blocking IL-2 signaling transduction

mTOR inhibitor approved to treat advanced renal carcinoma and used in organ transplant

everolimus

why does everolimus only inhibit mTORC1 and not mTORC2

mTORC2 can lead to feedback activation of Akt and lead to cancer

what are the rapalogs

sirolimus, temsirolimus, deforolimus, everolimus