As part of SGC-UNC’s scaffold hopping strategy to identify new series of compounds active against CaMKK2, we recently submitted a select number of compounds differing in hinge-binder for CaMKK2 enzyme inhibition assay. The hinge-binders included thienopyridine, furopyridine, quinoline, thienopyrimidines, pyrimidine, N-methyl azaindoles and quinazoline, Figure 1. Others are azaindoles, triazolopyridazine, pyrazolopyridine, imidazopyridine etc.
Figure 1: Examples of hinge-binders for scaffold hopping
For this exercise, we are also interested in obtaining a kinome-wide scan data (selectivity data) for CaMKK2, in addition to exploring the entire kinome space to identify hits against new kinases and expand on the inhibition profiles in our drug discovery efforts. Thus, a selected number of compounds, based in part on their CaMKK2 inhibitory activity are in the process of being sent to DiscoverX for a broad kinome scan.
Currently our two (2) leading scaffolds for CaMKK2 which continues to see expansive SAR are furopyridine and quinoline, where we continue to drive down the enzyme inhibition IC50’s of both series:
Starting from the non-substituted pyridine ring, YL-166-1/BE2-158, Figure 2, more than one hundred (100) analogs have been prepared, with greater than ten (10) analogs having IC50’s below 100 nM. The current best compound, BE2-124, has an IC50 of 14 nM.
Figure 2: Furopyridine SAR
Based on current percent of control (PoC – enzyme activity remaining after treatment) data received for previously synthesized analogs, we are anticipating single digit nanomolar IC50’s when they are finally generated. Compound YL-36-1, one of our earliest compounds to be synthesized, was recently declared a probe for CaMKK2, having met the criteria.
We have prepared more than seventy-five (75) analogs and currently working to improve upon the physicochemical properties of this series, particularly solubility. However, we are excited to report that the series exhibit strong inhibitory of CaMKK2. Selected compounds with their enzyme inhibition data are provided ins Figure 3.
Figure 3: CaMKK2 inhibition data from quinoline series
Are these Compounds Selective for CaMKK2?
Kinome-wide scan data on selected compounds indicates that both series (furopyridine and quinolines) have good selectivity. I will be discussing some of these interesting biological activities and how they relate to our SAR strategies in the coming months.
What about the Thienopyridines?
Recent enzyme inhibition data received for our scaffold hopping exercise revealed some very interesting inhibition profiles. Scaffolds that exhibited good CaMKK2 inhibitory activity include thienopyridine, quinazoline and pyrimidine, but most intriguing is the thienopyridine (BE2-217), Figure 5.
Figure 5: Selected compounds from scaffold hopping pool
Although thienopyridines and furopyridines would exhibit different binding orientations in exerting their inhibitory effects, we could draw comparisons in activity between compounds BE2-217 and YL-10-1, owing to the similarity in substitutions – to suggest that the thienopyridine series could also lead to the identification of yet another more potent, and perhaps ‘selective’ series of CaMKK2 inhibitors. However, only a limited number of analogs have been synthesized so far in the series. We anticipate that, the SAR strategy being adopted would lead to the discovery of a more potent and ‘selective’ compounds for CaMKK2.
To this end, compound BE2-217, together with other selected compounds are being sent for x-ray crystallographic studies with CaMKK2, and samples are also being sent to Analiza for solubility, microsomal stability and permeability tests.
It is hoped that these parameters (compound developability data) would guide the design and synthesis of compounds, not only in the thienopyridine series, but also our current leading series and may lead to the discovery of a compound that can ultimately be dosed into animal models.
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