CHI’s
Discovery on Target took place in Boston last week. With >1300 attendees
from over two dozen countries, this is the older, larger cousin of the San
Diego DDC meeting; at some points ten tracks were running simultaneously.
Although more heavily focused on biology, there were still plenty of talks of
interest to fragment folks.
Michael Shultz
(Novartis) provocatively asked “do we need to change the definition of
drug-like properties?” Long-time readers will recall that his earlier papers on
ligand efficiency led to considerable debate, which seems to have been settled to
everyone’s satisfaction with the exception of Dr. Saysno.
His new study,
which has just published in J. Med. Chem.,
analyzes the molecular properties of all 750 oral drugs approved in the US between
1900 and 2017. Contrary to what strict rule of five advocates might expect, the
molecular weight has increased over the past couple decades, as has the number
of hydrogen bond acceptors. In contrast, the number of hydrogen bond donors (#HBD)
has remained constant, suggesting that this may be more important for oral
bioavailability. (Indeed, #HBD is the only Lipinski rule not broken by
venetoclax.) Although Shultz did not examine “three dimensionality,” he
laudably includes all the raw data – including SMILES – in the supporting information.
This will be a useful resource for data-driven debates.
Molecular
properties are carefully considered by Ashley Adams, who discussed the four fragment
libraries used at AbbVie. The first is a 4000-member “rule of three” compliant
library. For tougher targets, a 9000-member Ro3.5 library is available, as is a specialized fluorine library for 19F NMR (2000 members) and a
1000-member “biophysics” library, in which all compounds are less than 200 Da.
Fragment optimization is often challenging, and since the C-H bond is most
common but perhaps least explored, the AbbVie database is annotated with
references on C-H bond activation relevant to each fragment.
Anil Padyana
spoke about the metabolic enzymes being targeted at Agios. As we mentioned
recently, these are very difficult targets, so the researchers often use
parallel (as opposed to nested) screening using different techniques to
minimize false negatives. Anil also described an interesting SPR assay in
which fragments were introduced to the protein after the addition of an
activating substrate.
High-quality
protein constructs are essential for any fragment screen, and Jan Schultz described
ZoBio’s technology for generating these. The company’s “protein domain trapping”
approach entails high-throughput generation and screening of tens or hundreds of
thousands of truncations of a given protein and rapidly selecting stable,
high-expressing, and active variants.
Trevor Perrior
mentioned that Domainex has a similar technology, which has been able to
produce soluble protein domains in 90% of its attempts. Trevor also described a
separate project in which a 656-fragment compound library was screened using SPR
against the enzyme RAS. They found fragments that bind in a previously discovered
site but, unlike the earlier work, the Domainex researchers were able to
optimize these to nanomolar inhibitors.
Another
success story was presented by Dean Brown (AstraZeneca), who described a collaboration
with Heptares to discover inhibitors of protease-activated receptor 2 (PAR2).
As the name suggests, this GPCR is activated when a protease cleaves the
N-terminus, allowing the remaining N-terminal residues to fold back and
activate the GPCR. The researchers used a stabilized form of PAR2 in an SPR
screen of 4000 fragments and obtained >100 binders in multiple series. This led
to AZ8838, which blocks signaling by binding in an allosteric pocket. It also
has a slow off-rate, which is often an attractive feature – particularly in the
context of intramolecular activation.
A number of
talks were focused on protein degraders such as PROTACs (PROteolysis-TArgeting
Chimeras). These are generally two-part molecules connected by a linker: one
part binds to a target of interest, while the other engages the cellular
degradation machinery to destroy the target. As Shanique Alabi, a graduate
student in Craig Crews's lab at Yale demonstrated, the molecules are catalytic –
a single PROTAC molecule can cause the destruction of multiple copies of a target
protein. This “event-driven” pharmacology is thus different from most
historical drugs, which are “occupancy-driven.” Is there a role for fragments?
One of the strengths
of FBLD is that if a ligandable site exists, it can be found. As Astex
demonstrated, the majority of proteins seem to have secondary
sites, away from the active site. Although some of these may be allosteric,
others probably have no functional activity, particularly in the case of
protein-protein interactions where secondary sites may be located some distance
from the interface. The power of degraders is that non-functional sites can be
made functional. The power of FBLD is that it can find small-molecule binding
sites, which could then be used as anchoring sites for one side of a degrader.
Watch this space!
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