Multivalent fragments in the clinic: Muvalaplin
It’s been a couple years since Practical
Fragments last updated our “fragments in the clinic” list. Before doing so it makes sense to highlight some of those we’ve missed. Let’s start
with an open-access Nature paper from Laura Michael and collaborators at Lilly and
Monash University published in 2024. Truth be told I’ve been waiting for a
longer discovery paper, but I’ll go with what’s available now.
The researchers were interested
in lipoprotein(a), or Lp(a), which has been linked to cardiovascular diseases. Lp(a)
forms when low-density lipoprotein (LDL) binds to apolipoprotein(a), or apo(a).
This is a two step process, in which the ten subtypes of so-called Kringle IV (KIV)
domains in apo(a) bind to lysine residues on LDL, followed by disulfide bond
formation between apo(a) and LDL. Blocking
the first step in this process should reduce levels of Lp(a).
Here's the only description of
the initial screen: “Biochemical and biophysical
compound screens using purified apo(a) KIV7-8 protein identified interacting
small molecules. Optimization of the initial binding molecules led to…LSN3353871.” Whatever the details, LSN3353871 is unequivocally a rule-of-three
compliant fragment. It is also a very ligand-efficient binder with high nanomolar affinity for the KIV8
domain. LSN3353871 disrupted the formation of Lp(a) in vitro at low micromolar levels and
decreased levels of Lp(a) in cynomolgus monkeys when dosed orally.
As noted above, the apo(a)
protein contains multiple KIV domains, and a classic method for
improving potency is by making dimeric ligands that can bind to two domains
simultaneously. The researchers did just this in the form of LSN3441732, which binds
to apo(a) and disrupts formation of Lp(a) in vitro at picomolar concentrations.
If dimeric ligands are better
than monomeric ones, why not go for multimeric ligands? The trimeric molecule LY3473329,
or muvalaplin, was synthesized and crystallographically shown to bind to three
copies of KIV8. It blocked formation of Lp(a) in vitro and reduced
Lp(a) levels in cynomolgus monkeys.
Kringle domains are found not
just in apo(a) but also in plasminogen, the zymogen form of plasmin, which is responsible
for degrading blood clots. Fortunately, subtle differences between the Kringle domains
in apo(a) and human plasminogen provide selectivity for the former protein,
especially for multivalent ligands such as muvalaplin, and a phase 1 clinical
study showed that Lp(a) could be lowered without affecting plasmin activity.
This is a nice application of
applying fundamental multivalent principles to develop a potent molecule. It is
also another example of a molecule that may not look like a drug but works like one: despite containing four basic nitrogen atoms,
three carboxylic acid moieties, and sporting a molecular weight above 700 Da, muvalaplin
is orally bioavailable. It is currently in a phase 3 trial in up to 10,450
patients. Cardiovascular disease is the leading cause of death in the developed
world, and Practical Fragments wishes luck to everyone involved in these
studies.
In the meantime, watch for more Practical
Fragments posts on new entries to our fragments in the clinic list, which
will be updated later this year.