LP99 : Antagonist of BRD9, BRD7
Protein target names: BRD9, BRD7
Mechanism of action: Antagonist
In Vitro Validations
DOI Reference: 10.1002/anie.201501394
In Cell Validations
In Vivo Data
No in Vivo Validations
LP99 is a selective inhibitor of BRD9 (KD = 99 nM) and BRD7 (KD = 909 nM) with good selectivity against a panel of 48 bromodomains at 10 uM and with cellular activity in the low uM range. The availability of an inactive enantiomeric control compound is beneficial. Although other BRD9 inhibitors, which may be more relevant for the investigation of BRD9 inhibition in model systems, have since been discovered, LP99 is a useful additional chemotype which can be used for confirming on-target effects.
LP99 is the first published selective inhibitor of BRD9 and BRD7 (ITC Kd BRD9 = 99 nM vs. ITC Kd BRD7 = 909 nM). It is selective against a panel of 48 bromodomains, with only BRD9 and BRD7 showing significant binding when assayed by DSF with 10 μM compound. However, 1 uM LP99 only minimally influenced BRD9-dependent gene expression in AML cell lines, as reported by the Vakoc and co-workers (Nat. Chem. Biol. 2016). Since the development of LP99, other BRD9-selective inhibitors have been reported, such as I-BRD9 and BI-9564, that are more relevant as probes to further investigate BRD9 inhibition in cells and in vivo. LP99, nonetheless, could be used for comparison with the more-recently developed BRD9 and BRD7 inhibitors in cellular assays.
The chemical probe LP99 was the first in its class, and this was an important achievement. The Structural Genomics Consortium (SGC) has setup a list of criteria for chemical probes. Two of these are in vitro potency <100 nM and significant cell activity at 1 micromolar. This chemical probe meets these criteria but is at the lower limits of in vitro and cellular potency. Since LP99 was introduced (in December 2014), there have been two additional BRD9/7 chemical probes, BI-9564 and TP-472, and a selective BRD9 chemical probe, I-BRD9. These all have different chemotypes and while they are all commercially available, only TP-472 has a control compound (TP-472N) that is also commercially available. (The inactive enantiomer of LP99 is not commercially available.) Both I-BRD9 and BI-9564 have (published) in vitro off-target activity on CECR2. Given the range of chemotypes and potencies available, it is recommended to use TP-472 in initial screens then follow-up hits with TP-472N (inactive control for TP-472) and LP99.