Druggable
Target molecules must have domains within their structures that drugs attack
Potential molecular targets (oncoproteins) are categorised as those that are
druggable and those that are not!
Druggability
A protein is considered druggable if it carries an identifiable enzymatic function - a well-defined catalytic cleft that it uses to carry out this function
Undruggable
Proteins lacking such catalytic clefts are often dismissed as being "undruggable”
transcription factors are widely thought to be undruggable
they usually lack catalytic clefts
A drug binding to the catalytic cleft of the a tyrosine kinase domain
PI3K
The presence of catalytic function does not guarantee a drug target
e.g. the Ras oncoprotein
has a clearly identifiable catalytic activity - its GTPase function
This enzymatic activity has never been the object of drug development, because the GTPase functions as negative regulation
Its inhibition would only augment the already-disastrous effects of amino acid substitutions that create Ras oncoproteins
The same can be said of some tyrosine phosphatases
whose designated role is to reverse the effects of growth-promoting tyrosine kinases
An exception to “druggability”
Nuclear hormone receptors (that also act as transcription factors) such as the estrogen and progesterone receptors have hormone-binding domains
these receptor proteins are vulnerble to disruption by pseudo-ligands
such as tamoxifen
Can drugs disrupt protein-protein interactions (PPI)
Identifying PPI networks has been a hot topic in molecular biology
Small examples of PPI in this network are:
SH2/Tyr-OH
Cyclin/CDK
Rb/HDAC
GRB-2/SOS
Protein protein interactions
Most attempts at preventing PPI through custom- made drug molecules have been unsuccessful.
Why? because the association of two domains with one another involves multiple points of contact.
These points of contact extend over molecular domains that exceed the dimensions of drug molecules
Inhibitors of protein-protein interactions
A search for compounds that inhibit Mdm2-p53 binding resulted in the discovery of Nutlin-2, which associates with the p53-binding pocket of Mdm2
The healthy effects from tea have been ascribed to constituents which induce apoptosis in tumor cells at very low concentrations.
e.g. Epigallocatechin gallate binds an important anti-apoptotic protein Bcl-X
