The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit
protein kinases that phosphorylate
serine or
threonine residues and can discriminate between the kinase domains of the EGFR and that of the
insulin receptor. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative
HER2.[2][3]
Development of drugs
Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-
tumor agents and anti-
leukemic agents.[4][5] Based on this work
imatinib was developed against
chronic myelogenous leukemia (CML)[6] and later
gefitinib and
erlotinib aiming at the EGF receptor.
Dasatinib is a
Src tyrosine kinase inhibitor that is effective both as a
senolytic and as therapy for CML.[7]
Adavosertib is a
Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors.[9] However, toxicities such as
myelosuppression,
diarrhea, and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug.[10]
Lapatinib, FDA approved for treatment in conjunction with chemotherapy or hormone therapy, is also currently undergoing clinical trials in the treatment of
HER2-overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing. A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea.[11]
Mechanisms
TKIs operate by four different mechanisms: they can compete with
adenosine triphosphate (ATP), the phosphorylating entity, the
substrate or both or can act in an
allosteric fashion, namely bind to a site outside the active site, affecting its activity by a
conformational change.[12] Recently TKIs have been shown to deprive
tyrosine kinases of access to the
Cdc37-
Hsp90 molecular chaperone system on which they depend for their cellular stability, leading to their
ubiquitylation and degradation.[13] Signal transduction therapy can also be used for non-cancer proliferative diseases and for inflammatory conditions.[14] An example is
nintedanib for the treatment of
idiopathic pulmonary fibrosis.[15]
^Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A (1991). "Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases". J Med Chem. 34 (6): 1896–907.
doi:
10.1021/jm00110a022.
PMID1676428.
^Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM (1996). "Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor". Nature. 379 (6566): 645–8.
Bibcode:
1996Natur.379..645M.
doi:
10.1038/379645a0.
PMID8628398.
S2CID2528506.
^Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat Med. 2 (5): 561–6.
doi:
10.1038/nm0596-561.
PMID8616716.
S2CID36102747.
^Posner I, Engel M, Gazit A, Levitzki A (1994). "Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program". Mol. Pharmacol. 45 (4): 673–83.
PMID8183246.