Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment
Wei Long et al
This paper in the August addition has promoted a little bit of a SHP2 inhibitor profile – so more a suite of papers than a paper of the month…
There are two big problems in small molecule drug discovery
i) Well validated biological targets and
ii) quality hit matter.
We are not going to comment on i) here; another big discussion another time. SHP2 is an example of what happens when quality chemical matter (ii) is found for a previously ‘undruggable target’.
SHP2 proteins have been known for some time to be good targets for inhibition to restrict cell signalling and growth. Multiple attempts found quality chemical start points had only yielded highly charged compounds that could not be optimised. Hence the target went into the ‘undruggable’ category. As has happened before, once some chemical matter is found, suddenly the target IS druggable and the industry leaps on the targets. It was some years ago that Novartis tirelessly worked at finding an allosteric binding site that would yield the same effect as inhibition of the main site BUT with a quality chemical start point. They succeeded and so drug discovery went into overdrive.
This latest publication is one of those “fast following” projects, leading to JAB-3312. If you have followed the SHP2 world, then it is good to see the medchem paper come out. The write up describes the starting points and acknowledges the work of others, and in-house Structure Based Drug Design to find a novel pyridine warhead group. The program works through maximising in-vitro potency (key being p-ERK inhibition downstream) and minimising hERG. The candidate itself does inhibit hERG at 4.4uM but the margin to potency is good, and in-vivo safety tox showed the effect was minimal. Of advantage is co-dosing the compound with a K-RAS inhibitor.
As an education to readers who are newer to medchem, here are a select set of SHP2 inhibitor papers. These give an overview of how this area evolved over time.
Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor.
Garcia Fortanet, J.; Chen, C. H.; Chen, Y. P.; Chen, Z.; Deng, Z.; Firestone, B.; Fekkes, P.; Fodor, M.; Fortin, P. D.; Fridrich, C.
Dual Allosteric Inhibition of SHP2 Phosphatase.
Matthew J. LaMarche et al
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors
Matthew J. LaMarche et al
Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer
Matthew J. LaMarche et al
A patent review of SHP2 allosteric inhibitors (2018-present)
Alessia Petrocchi, Alina Ciammaichella