532 Lec 20

Gleevec/imatinib

ABL tyrosine kinase - first med of a new class that specifically targets tyrosine kinases

dasatinib/Sprycel

→ BCR/ABL, SRC, & c-Kit kinases - for mostly all Gleevec resistant pts

nilotinib/Tasigna

→ BCR/ABL, c-Kit, MAPK11, & PDGFRB kinases - for Gleevec resistant pts

Torisel/temsirolimus:

Bind to FK506-binding protein 12 (FKBP12) → mTOR inhibition

vemurafenib/Caprelsa:

Use: BRAFV600E + metastatic melanoma

Inhibits BRAF, MEK, & ERK

crizotinib/Xalkori:

Use: late stage non-small cell lung cancer (NSCLC)

Targets mutated anaplastic lymphoma kinase (ALK)

trametinib/Mekinist: 

Use: unresectable/metastatic melanoma and combo w/ dabrafenib for melanoma

Targets BRAF V600E or V600K mutations

dabrafenib/Tafinlar:

Use: unresectable/metastatic melanoma and combo w/ trametinib for melanoma

Targets BRAF V600E mutation

ibrutinib/Imbruvica:

Use: chronic lymphocytic leukemia (CLL)

Selective covalent inhibitor for Bruton’s tyrosine kinase (BTK)

Michael acceptor ~ only covalent inhibitor

tofacitinib/Xeljanz or Jakvinus:

Use: Rheumatoid arthritis + pts who don’t respond to methotrexate

Janus kinase inhibitor

Philadelphia Chromosome:

This chromosome is abnormal (result of translocation) and

Contains the gene encoding for a CML fusion protein (BCR/Abl) → Causes CML

Why is the resulting fusion protein BCR/ABL such a good target for Gleevec?

→ Not found in healthy people, so you can achieve high selectivity

Know how gleevec works and the structural basis for its ability to bind to the inactive conformation of BCR/ABL kinase but not the active conformation.

→Binds to the ATP binding site of ABL

→Inhibits the ABL tyrokinase domain

→Gleevec preferentially binds to the inactive conformation of BCR/ABL. This specificity is due to the drug's structure, which fits the shape and configuration of the ATP-binding site only when BCR/ABL is in its inactive form.

The molecular arguments relating to the different IC 50 values displayed for gleevec and dasatinib (Sprycel) that supported the change in dasatinib and nilotinib from being 2nd line CML therapeutics to being 1 st line CML drug

Smaller IC50= more potent

Dasatinib: Smaller IC50, so its more potent that Gleevec

dasatinib binds both wild type and the gleevec resistant form of BCR/ABL

(with T315A mutation) much better than gleevec (up to 100 fold better in the wild type

case).

basically theres resistance to gleevac so now Dasatinib and nilotinib are preferred

Of gleevec resistant strains of CML which mutations have proven the most difficult to deal with?

→ V299L, T315I, T315A

Bosutinib

inhibits cell lines over expressing Bcr-Abl

EXCEPT T3151I or V299L mutations

Ponatinib

Has activity against T315I mutants but it is too toxic 

Bafetinib

Not effective against certain mutations like T315I

Axitinib

Inhibits T315I mutation and well tolerated

Omacetaxine

Reversibly inhibits protein sythesis that facilitates tumor cell death

—>independent of Bcr-Abl singlaing pathway