BETting on fast follower fragments

A common approach in drug discovery is to improve a previously reported molecule. An example of such a “fast follower” approach has just been published in J. Med. Chem. by Cheng Luo, Bing Zhou, and colleagues at Shanghai Institute of Materia Medica.

The researchers were specifically interested in bromodomains, which recognize acetylated lysine residues in proteins and play major roles in gene expression. In 2018 we described AbbVie’s fragment-based discovery of ABBV-075, which had entered phase 1 clinical trials. Although reasonably selective for BET-family bromodomains, it also strongly inhibits EP300, which could lead to toxicity. Thus, more selective molecules have been sought.

The new paper starts with a thermal shift assay of 1000 fragments against the two separate bromodomains of BRD4, BD1 and BD2. Hits were validated using an AlphaScreen assay. Compound 47 was found to be active against both BD1 and BD2, with high ligand efficiency (all IC₅₀ values shown are for BD1; values for BD2 are similar). Modeling suggested this fragment could be merged with ABBV-075, and indeed the resulting compound 26 was quite potent. (Note: structures of compounds 26 and 38 were originally drawn incorrectly - now fixed.)

Compound 26 was metabolically unstable, but further optimization, aided by crystallography and modeling, ultimately led to compound 38. This molecule has good oral bioavailability in mice and promising pharmacokinetics in both mice and rats. It inhibits the expression of cancer-driving genes such as c-Myc and BCL-2, inhibits the growth of several cancer cell lines, and demonstrated good tumor growth inhibition in a mouse xenograft study. Compound 26 does not inhibit five cytochrome P450 enzymes or hERG. Finally, it is much more selective than ABBV-075 against EP300 and indeed most other bromodomains aside from BET family members. The researchers conclude that “compound 38 is a highly promising preclinical candidate.”

Unfortunately, selectivity for BET-family bromodomains may not be sufficient to avoid toxicity. Indeed, as we described earlier this year, AbbVie has dropped clinical development of ABBV-075 in favor of ABBV-744, which is selective for BD2 over BD1. Whether or not the same could be done for this series, the paper is still another nice example of appending a fragment onto a previously discovered molecule.