Bumped-Kinase Inhibitors: A New Path Toward Treating EPM in Horses

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A small structural “bump” on a molecule might be the big breakthrough EPM care has been waiting for. We sit down with researcher and clinician Izabela de Assis Rocha to unpack how bumped kinase inhibitors exploit a tiny difference between parasite and mammalian kinases to hit Sarcocystis neurona where it hurts—motility, invasion, and replication—while sparing the horse. It’s a molecular strategy with practical promise, and the conversation bridges the stall, the lab, and the future of equine neurology.

We break down the science behind CDPK1, the gatekeeper residue that drives selectivity, and why unique parasite structures like the apical complex and apicoplast open new therapeutic lanes. Then we move into what really matters for care: pharmacokinetics and clinical fit. BKI-1708 shows strong systemic distribution that positions it as a prophylactic candidate, while early data on BKI-1553 suggests better CNS penetration and a path toward active EPM treatment. Isabella explains how EPM’s dead-end host biology may lower the risk of widespread resistance, a rare bright spot in the antiparasitic landscape.

Clinical trials are the hard part. With no robust experimental infection model and fewer than 1% of exposed horses developing disease, enrolling enough cases takes patience and teamwork. We talk about building pragmatic, clinician-led studies, harmonizing diagnostics and neurologic scoring, and tracking relapse to find outcomes that matter to horses and owners. The One Health angle also shines through: BKIs show activity against equine piroplasmosis and have potential roles in toxoplasmosis and cryptosporidiosis, linking equine research to human and livestock health.

If you care about evidence-based equine neurology, new antiparasitic strategies, and turning elegant biochemistry into barn-side change, this is your roadmap. Subscribe, share with a colleague who manages EPM cases, and leave a review to help more veterinarians find the show. What question would you ask about bringing BKIs into practice?

AJVR article: https://doi.org/10.2460/ajvr.25.07.0270

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Episode Transcript

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SPEAKER_03 (00:35):
Welcome to Veterinary Vertex, the AVMA
Journal's podcast, where wedelve into the behind-the-scenes
look with manuscript authors.
I'm editor-in-chief LisaFortier, joined by the fabulous
associate editor Sarah Wright.
Today we're discussing bumpedkinase inhibitors in horses for
the prevention and treatment ofEPM, which is equine protozoan
myelitis, with author IsabellaRocha.

(00:58):
Hey Isabella, thanks for beinghere with us today to talk about
my favorite species, the horse.
Thank you for the opportunity todiscuss this research.

SPEAKER_01 (01:06):
We're so happy to have you here today.
Thanks for joining us.
So let's get started.
So before we dive in, could youshare a little bit about your
background and what brought youto EPM research?

SPEAKER_02 (01:16):
So, since early when I started vet school, I became
very interested in horses andurology in general.
I had an opportunity to attendone of Steve's lectures on EPM
when he visited Brazil.
And that's when I knew that'swhat I wanted to work on, being
able to put together horses andurology.

SPEAKER_03 (01:35):
Isabella, your AJVR article discusses the potential
utility of bump kinaseinhibitors for the prevention
and treatment of EPM.
What's the background on thisresearch?

SPEAKER_02 (01:46):
So historically, protein kinase inhibitors were
considered for therapy ofparasitic diseases, but the
challenge of specific inhibitionof parasite kinases versus the
mammalian kinases had limitedthe practical application.
So in the case of the bumpedkinase inhibitors, uh, they were
originally generated to buildspecificity into this drug class

(02:10):
to compete with the ATP for thekinase active site.
The bump on the BKIs uhprecludes there to bind to
almost all mammalian kinases,because those have a bulky uh
gatekeeper residue in the ATPbinding pocket.
So West Lab uh at the Universityof Washington were able to

(02:32):
determine that the Picomplexinparasites have a naturally
occurring small gatekeeperresidue in their ATP binding
site, and that is on a proteincalled calcium-dependent protein
kinase 1 that we called CDPK1.
This is a protein important forparasite motility, host cell
invasion, and decres.

(02:53):
Considering that, they embarkedon a medical chemistry project
to optimize BKIs for use againstseveral apicomplex species,
including sarcocystisousneurona.

SPEAKER_03 (03:03):
Yeah, really thorough answer.
So you've answered a lot of myfollow-up questions, but does
the biology of sarcocystisneurona create challenges or
provide opportunities for BKIs?

SPEAKER_02 (03:14):
Yes, sarcocystis neurona is a single-celled uh
eukaryotic parasite.
Uh, this means that it relies onmany metabolic pathways shared
with mammals.
And that is a challenge toidentify selective drug targets.
Thankfully, this parasite alsohas many unique features that
are not shared with mammals,such as what we call the apical

(03:35):
complex, which is involved inthe process of motility and
invasion of the host cells, andit also has a unique organelle
called the apicoplast, that is avestigial non-photosynthetic
plastid, and that's involved infatty acid biosynthesis.
So the presence of these uniquestructures, they are promising
for targeting these parasites.

SPEAKER_01 (03:56):
So, Isabella, what are the key take-home messages
you hope veterinarians willremember?

SPEAKER_02 (04:01):
I believe this research is a great example of
how foundational studies inparasite biology inform
translational research.
Uh, without sequencing theZaccousitis Neurona genome and a
lot of the in vitro studies, theBKIs wouldn't have advanced to
pharmacokinetic studies inhorses.
So, foundational study may takea long time to lead to the

(04:21):
clinical applications, but itoften leads to the great
advantage advancements in ourfield.

SPEAKER_03 (04:27):
Isabel, are there concerns around drug resistance
with BKIs like there are withother antiparasitic treatments?

SPEAKER_02 (04:35):
Uh so it's interesting uh because in the
psychostatisms aurona lifecycle, horses they're at
dead-end holstices in which onlya sexual reproduction occurs.
That this means that the use ofthe drugs in the parasites are
unlikely to lead uh into theresistance.
That means that infection is nottransmitted from one horse to

(04:58):
another.
So even if the resistance occursat the individual horse, it's
not going to become widespread.
And we need to consider that theparasites they replicate very
slowly over a course of manydays.
Uh so they are very careful whenthey are uh multiplying and
dealing with their genome.
So mutations are unlikely tooccur in these uh parasites.

(05:20):
Uh so even if it were at thehorse level, we think it's
unlikely that resistance wouldoccur, which is very interesting
considering the biology.

SPEAKER_03 (05:29):
Yeah, very cool.
You talked about this or touchedon a little bit earlier, but
maybe a little bit more.
Do BKI show promise againstother equine pathogens or even
human diseases caused by relatedparasites?

SPEAKER_02 (05:42):
Yes, absolutely.
So in horses, the BKIs are alsoeffective against Babise Cavalli
and Telluria equi, which are thecauses of equine
throughplasmosis.
Uh, and this drug class has alsobeen investigated for the
treatment oftoxoplasma-associated abortion
in sheep, toxoplasmosis, andcryptosperidiosis in humans.

(06:03):
So it's an example of uh onehealth research for sure.

SPEAKER_01 (06:07):
Yeah, I love that one health tie-in.
Thanks for providing that.
And looking ahead, what are thenext steps for research in this
area?

SPEAKER_02 (06:13):
So the current lead compound, BKI1708, has a great
systemic uh distribution inhorses, but it has low CNS
penetration.
So it's a very promisingcompound for prophylaxis as it
can control systemic infection,but it may not be suitable for
EPM treatment at this point.
So after we published thispaper, we started some

(06:34):
preliminary uh work with adifferent lead called uh
BKI-1553.
And so far, we were able to showum very good drug levels on CSF,
which means that this compoundmight be more suitable for um
treatment than what we havestudied so far.
Um, so hopefully, with uh morePK experiments, uh, this other

(06:57):
lead compound could potentiallyadvance to a clinical trial in
horses with EPM.

SPEAKER_01 (07:02):
Very cool.
And how do you envisioncollaborating with clinicians or
other researchers to advancethis one health work?

SPEAKER_02 (07:09):
So, the main challenge with EPM clinical
research is that we do not havea robust experimental infection
model.
That means that we need to workwith naturally occurring EPM
cases, and for that, we need toum work with the clinicians.
Uh, the main challenge is thatless than 1% of the horses
exposed to sarcosys develop EPM.

(07:32):
So it takes a long time toachieve a good sample size in a
clinical trial.
And we also struggle uh withtesting the efficacy of
prophylactic um uh approaches.
So working with the clinicians,not only in recruiting horses
for this type of study, but alsobrainstorming ways that we could
assess uh how prophylacticapproaches help horses.

(07:55):
That is certainly veryimportant.

SPEAKER_01 (07:57):
And how might future findings translate into
practical changes in day-to-dayveterinary practice?

SPEAKER_02 (08:04):
So we hope that the BKIs would eventually lead to a
commercial product, which wouldprovide a third treatment option
for uh EPM?
This would be especiallyimportant for treating horses
that either do not respond wellto the current Antaprotozoas or
animals that tend to relapseafter treatment completion.

SPEAKER_03 (08:23):
Isabella, let's talk a little bit about your journey.
How did your training, all theway from uh interest in becoming
a veterinarian and your previouswork prepare you to uh come up
with this idea, implement thestudy, get across the finish
line all the way throughpublication and write this
article?

SPEAKER_02 (08:42):
Uh so it's been uh, as I mentioned, since vet
school, I became interested uhin neurologic diseases of
horses.
And it was especially for meduring residency that I started
treating uh the neurologiccases, and it that became clear
that compared to all otherdiseases that we see in horses,
the neurologic diseases are themost challenging ones.

(09:03):
And even in the case of EPM,which is a disease we know a lot
about how to diagnose and treat,there is still uh shortcomings
with that.
So it was not only my interestin the quine neurology, but also
the day-to-day struggle as aclinician that led me to pursue
uh training and research in thisarea.

(09:23):
And it was very interesting forme as I was studying uh the
success rate and the relapserate for the current treatments
for EPM, and they are about thesame for uh the different drug
classes that we had.
So trying to develop a newproduct that had the potential
to have a superior um successfulrate in voices that would was

(09:45):
very appealing uh to me.

SPEAKER_03 (09:48):
Yeah, it's surely a frustrating disease, those
shortage of experiments thatneed to be done.
And it it is interesting that wecan't really replicate it uh in
a clinical model.
Yes.
Yeah, certainly hampersprogress.
Yes.
Were there any mentors orcolleagues that play the pivotal
role in guiding your thinking orthese research methods in this
article?

SPEAKER_02 (10:09):
Absolutely.
So both uh Steve and then uhwere great.
Uh so Steve's just the amazingneurologist, and he's been my uh
great mentor on the clinicalside of this research, and he's
the person I look up to as aclinician.
But also my uh PhD mentor, uh,then he's also for me the role

(10:32):
model as a scientist.
So it's very interestingbecause, as a clinician, as
we're trying to diagnose ananimal, we try to gather
evidence to support a diagnosisas we go through uh our
different uh differentialdiagnosis.
But as a scientist, it's alittle bit of the opposite as we

(10:53):
try to prove ourselves wrongbefore we move forward.
So we want to do a great numberof experiments and test all the
possibilities before we can say,yes, this is the direction we
need to forward.
So it's learning to think indifferent ways and blending
being a clinician and ascientist is certainly being

(11:13):
very interesting.
And I'm grateful to my mentorsfor that.

SPEAKER_01 (11:17):
Now, before we wrap up, let's have a little bit of
fun.
So we have two fun questions foryou today, Isabella.
First one is about communicatingwith animals.
So if you could instantlycommunicate with any one
species, which would you pick?
And what's the first thing youwould ask them?

SPEAKER_02 (11:32):
I would pick dogs, and the first thing I would ask
is what do they dream about?
Sometimes it just looks likethey're having fun, and I wonder
if they're just reliving theirday or prepping for the next
day, and but also knowing whatin nightmares look like, what
they have to worry about so muchthat they have nightmares.

SPEAKER_03 (11:53):
I like the dreaming one.
I'm not so sure I want to knowabout the nightmares.
Maybe I pet them too fast, cameat them too fast, didn't let
them out enough.
On the human side, if you caninstantly master any skill
related to patient carebehavior, uh, what would you
choose?

SPEAKER_02 (12:13):
Certainly they spinal taps.
Uh as Steve likes to say,whoever says they never
struggled with a spinal tap,haven't done enough spinal taps.
Every once in a while we grab,we got a horse that is a little
bit crooked in their back, orwe're just not having a good
day.
So I like to think that spinaltaps are half technique and half

(12:33):
luck.
You never know.

SPEAKER_03 (12:35):
That's awesome and true.

SPEAKER_01 (12:38):
It's a very good answer.
Well, Isabella, thank you somuch for joining us.
We appreciate you being with ustoday and for sharing your work
too with AJBR.

SPEAKER_02 (12:46):
Thank you very much for the opportunity to share
this research.
It's very exciting to me, andI'm grateful for being able to
talk more about TPM, which I'mfascinated about.

SPEAKER_01 (12:57):
And for our listeners and viewers, you can
read Isabella's article on AJVR.
I'm Sarah Wright here with LisaFortier.
Be sure to tune in next week foranother episode of Veterinary
Vertex.
And don't forget to leave us arating and review on EPA
Podcasts or wherever you listen.