Tag Archives: CHRFAM7A

Why drug development is hard #32 and #33

The bloodbath among drug chemists continues (see Derek’s recent posts — https://blogs.sciencemag.org/pipeline/archives/2019/04/22/big-pharma-cuts-current-and-coming) because drug development is very hard and success is rare. Two nearly back to back papers in PNAS show just how hard drug development is (and why).

Animal models of human disease have a poor track record in pointing to new drugs.  One reason is that humans have new genes that animals don’t. One example is the horribly named CHRFAM7A, a dominant negative inhibitor of the alpha7 nicotinic cholinergic receptor [ PNAS vol. 116 pp. 7932 – 7940 ’16 ].

Alpha7 is found on macrophages where it exerts an anti-inflammatory action. Alpha7 agonists work beautifully in rodent inflammatory disease models.  They crashed and burned in human trials.  Why?  Because CHRFAM7A  binds to Alpha7 blocking the ability of acetyl choline to bind to it.  It is a totally new gene for man. It arose when 5 exons of the UL kinase 4 gene on chromosome #3 translocated nd then fused with the Dupa gene, which itself originated with 5 exons partially duplicated from the 10 exon alpha7 gene on the forward strand of chromosome #15.  So CHRFAM7A in close proximity to alpha7 (about which much more in the next post) and structurally similar to it.

[ PNAS vol. 116 pp. 7957 – 7962 ’19 ] Practically next door is a paper about MI-2, a drug thought to be useful in a (fortunately) rare brain tumor of childhood — diffuse intrinsic pontine glioma (maybe 3 cases in 38 years of practice).  Menin is a tumor suppressor lacking in a less rare syndrome (Type I Multiple Endocrine Neoplasia). MI-2 inhibits menin, but this paper shows that this isn’t its mechanism of action. Rather it inhibits an enzyme on the biosynthetic route to cholesterol (lanosterol synthetase).  So even when you think you know what a drug should be doing (which is probably why MI-2 was developed), that may not be how it works.