PHRM 542 Immune Suppression MedChem

Describe the importance of folic acid

An essential enzyme cofactor used for the transfer of methyl groups onto biomolecules

What is the MOA of methotrexate?

An "antifolate" that inhibits DHFR and prevents the synthesis of dTMP

What is the importance of the methyl group of MTX?

Prevents catalytic mechanism of methyl transfer

Which group on MTX increases the binding affinity to DHFR by ~1000x?

The amine

How is methotrexate actively transported into the urine?

By OAT3

What is critical for cellular activity of MTX?

Poly-glutamation by FPGS which helps retain MTX in the cells

Where does most of the sulfasalazine metabolism take place?

Primarily by bacterial enzymes in the colon

What drug should be avoided when using azathioprine and why?

Allopurinol should be avoided since it inhibits xanthine oxidase (XO)

XO converts 6-MP (active form of azathioprine) into an inactive metabolite

What is the role of TPMT in azathioprine metabolism?

Degrades active azathioprine metabolites = patients deficient in TMPT are at risk of toxicity from azathioprine

What is the MOA of mycophenolic acid?

Potent, reversible, non-competitive inhibitor of IMPDH

This inhibits de novo guanosine synthesis

What is the MOA of teriflunomide?

Inhibits DHODH, a key enzyme in the "de novo" synthesis of pyrimidines

What does cyclosporine bind to?

Cyclophilins

Cyclophilin-cyclosporine complex is an inhibitor of calcineurin

What does tacrolimus bind to?

Binds to FKBP12

FKBP12-tacrolimus complex is an inhibitor of calcineurin

Describe the metabolism of cyclosporine

CYP3A4 substrate and INHIBITOR

Use with caution with CYP3A4 substrates (ex: sirolimus and tacrolimus)

What is a significant concern with cyclosporine (and tacrolimus)?

Renal damage (nephrotoxicity)

Mechanism unclear

What drugs besides tacrolimus bind FKBP?

Sirolimus

Everolimus

Temsirolimus

What is necessary for calcineurin or mTor inhibition?

No inhibition of either target occurs without first binding to FKBP12

Portion on the right of the respective molecules is what inhibits calcineurin or mTor while the portion on the left if what binds FKBP12

What is the typical function of kinases?

Add a phosphate to a protein

Ex: tyrosine kinase adds phosphate to a tyrosine

Ex: serine/threonine kinase adds phosphate to a serine or threonine

What is always the phosphate donor of a kinase?

ATP

What do inhibitors of kinases usually bind to?

ATP binding pocket

What are the steps of typical kinase inhibitors?

1. Make an H-bond donor / acceptor interaction with the hinge

2. Reach into the hydrophobic pocket

3. Have some sort of solubilizing tail that reaches towards the specificity pocket

What part of JAK inhibitors is critical for binding to the hinge-domain of the ATP binding pocket?

H-bond donor-acceptor pair

Describe the metabolism of sirolimus

Demethylation by CYP3A4

Describe the metabolism of everolimus

Less CYP3A4 metabolism

Describe the selectivity of everolimus

More selective for one subtype of mTor vs. another

Describe the metabolism of temsirolimus

Esterase mediated metabolism to sirolimus (active metabolite)