- Updated preclinical data will be presented from Ryvu's
synthetic lethality pipeline, including PRMT5 inhibitors in
MTAP-Deficient cancers, WRN inhibitors for the treatment of
microsatellite unstable (MSI-H) tumors, and Ryvu's cutting-edge
synthetic lethality platform based on primary cancer
cells.
- Poster presentation to highlight the synergistic effects of
RVU120 in combination with ruxolitinib in myeloproliferative
neoplasms.
- Ryvu's partner Menarini to present data on MEN1703 (SEL24),
demonstrating promising anti-tumor activity in preclinical models
of myelofibrosis both as a single agent and combined with
ruxolitinib.
KRAKOW, Poland, March 6,
2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a
clinical-stage drug discovery and development company focusing
on novel small molecule therapies that address emerging targets
in oncology, announced today that preclinical data from its
synthetic lethality pipeline and RVU120 project, as well as on
MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual
Meeting, scheduled for April 5-10 in
San Diego, California.
"We are excited to present our latest preclinical data at
the AACR Annual Meeting, showcasing our significant progress in
advancing novel small molecule therapies for oncology. This
year, we will present data from our most advanced preclinical
project on MTA-cooperative PRMT5 inhibitors, the lead program
within Ryvu's synthetic lethality pipeline. Our PRMT5 inhibitors
have demonstrated remarkable efficacy and selectivity in
preclinical models of tumors with MTAP gene deletion, providing a
strong foundation for further development," said Krzysztof
Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics.
"Our discovery platform continues to produce novel precision
medicine targets and drugs, and we are proud to highlight platform
data based on primary cancer cells, specifically in colorectal
cancer models with broader applicability across cancers. "
Details on the poster presentations are as follows:
Abstract Title: "Discovery of novel MTA-cooperative
PRMT5 inhibitors as targeted therapeutics for MTAP-deleted
cancers."
Session Name: HDAC and Methyltransferase
Inhibitors Session date and time: Tuesday, April 9, 9:00 AM
- 12:30 PM EST
Poster Number: 4598
Co-deletion of MTAP is observed in approximately 80-90% of
tumors with homozygous deletion of CDKN2A, representing 10-15% of
all human tumors. These tumor types, including non-small cell lung
cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma,
have a poor prognosis, highlighting the significant unmet medical
need in this area. Deletion of MTAP leads to a significant
accumulation of methylthioadenosine (MTA) in cells. MTA, at high
concentrations, selectively inhibits the PRMT5 methyltransferase
enzyme. As a result, the overall level of symmetric arginine
dimethylation throughout the proteome is reduced, which makes cells
with MTAP deletion more susceptible to therapeutic targeting of
PRMT5. Ryvu has developed potentially best-in-class MTA-cooperative
PRMT5 inhibitors showing favorable drug-like properties and
effective PRMT5 inhibition dependent on MTA binding.
Structure-based lead optimization has enabled rapid expansion and
delivery of two independent chemical series with novel intellectual
property, characterized by high target engagement in cells, and
selective potency in MTAP-deleted cell lines, along with favorable
DMPK profiles allowing an oral administration. The antitumor
activities were compared in vitro and in vivo in MTAP
null tumors. The correlation between compound exposure and
on-target effect was confirmed in PK/PD and efficacy studies.
Performed studies confirm that MTA-cooperative PRMT5 inhibitors
exert a strong synthetic lethal phenotype in MTAP-deleted cancers,
offering an exciting therapeutic opportunity for a large patient
population.
Abstract Title: "A comprehensive platform for
identification of KRAS-specific synthetic lethal targets using
patient-derived cells."
Session Name: New Targets, Technologies, and Drug Delivery
Systems
Session date and time: Tuesday,
April 9, 9:00 AM - 12:30 PM EST Poster
Number: 4684
Ryvu's cutting-edge drug discovery platform uniquely combines
high throughput capabilities with the precision and translational
impact traditionally associated with later, lower throughput
stages. Our approach taps into the power of primary cells to
transform cancer treatment, focusing especially on colorectal
cancer (CRC). By leveraging human stem cell derived model cells
(PDC), patient-derived xenografts (PDXs) and clinical samples we
have created a groundbreaking approach to identify synthetic lethal
(SL) targets specific to oncogenic pathways. We integrate
CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and
whole-exome sequencing (WES), enabling rapid identification of
molecular vulnerabilities. We present results obtained in
engineered intestinal primary models which represent frequently
altered genes in CRC, including KRAS G12D mutation. Notably, our
use of normal hISCs facilitates the identification of genes
essential only for transformed cells, amplifying the precision
tumor targeting of our novel discoveries. Beyond CRC, our platform
could extend to personalized medicine approaches in various cancer
types. By spearheading the identification of KRAS-specific SL
inhibitors, we pave the way for novel, targeted therapies, offering
hope to patients battling this heterogeneous malignancy and
beyond.
Abstract Title: "Discovery of WRN
inhibitors as targeted therapy in the treatment of microsatellite
unstable (MSI-H) tumors."
Session Name: Novel Antitumor Agents 4
Session date and time: Tuesday,
April 9, 1:30 PM –
05:00 PM EST
Poster Number: 5942
The synthetic lethality resulting from the inhibition of the WRN
helicase protein has been observed in tumors characterized by high
levels of microsatellite instability (MSI-H). This instability
stems from a deficiency in the DNA mismatch repair (MMR)
mechanisms, leading to the accumulation of DNA damage. This
phenomenon is notably prevalent in 10-30% of colorectal, gastric,
endometrial, and ovarian cancers.
Structure-based optimization performed at Ryvu facilitated the
rapid expansion and delivery of a compound library with novel
intellectual property (IP), demonstrating target engagement in
cells and selective potency over other RecQ family members. The
pharmacokinetic properties of these compounds were favorable and
allowed progressing to in vivo studies which confirmed
efficacy of our compounds in xenograft MSI-H cancer
models. These data provide pharmacological proof-of-concept
for the synthetic lethal effect of our inhibitors and support WRN
inhibition as a new, targeted oncological therapy.
Abstract Title: "Combination JAK1/2 and
CDK8/19 inhibition demonstrates enhanced efficacy in
myeloproliferative neoplasms."
Session Name: Targeted, Combination, and Differentiation
Therapies
Session date and time: Wednesday, April 10, 9:00 AM - 12:30 PM
EST Poster Number: 7225
The presentation, prepared in collaboration with Prof. Raajit
Rampal's group from Memorial Sloan Kettering Cancer Center,
includes the assessment of RVU120, a highly selective and potent
CDK8/19 inhibitor, both in monotherapy and combination with
ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of
myeloproliferative neoplasms (MPN) and
hydroxyurea-resistant/intolerant polycythemia vera (PV). The
combination of RVU120 and RUX demonstrated biochemical synergy and
differential inhibition of STAT5 phosphorylation in vitro. Further,
in vivo treatment with RVU120/RUX+RVU120 resulted in significant
reductions in disease manifestation (splenomegaly, WBC, fibrosis
scoring, hematopoiesis) compared to VEH/RUX. These data suggest
that JAK1/2 and CDK8/19 inhibition could be a potential novel
therapeutic strategy in MPNs. Additional work on nascent RNA
expression and cytokine profiles aims at elucidating the exact
mechanism of synergy between tested compounds.
Abstract Title: "MEN1703/SEL24 exhibits
promising antitumoral activity in preclinical models of
myelofibrosis both as single agent and combined with
ruxolitinib."
Session Name: Novel Antitumor Agents 2
Session date and time: Sunday
April 7, 01:30 AM –
0500 PM EST
Poster Number: 665
MEN1703 (SEL24) is an oral, first-in-class, dual PIM/FLT3 kinase
inhibitor in development for hematologic malignancies. The
presented study aims to investigate the efficacy of MEN1703 alone
and in combination with the JAK inhibitor ruxolitinib (RUX) in
preclinical models of myelofibrosis (MF) and to elucidate the
underlying signaling pathways. MEN1703 demonstrated anti-tumoral
efficacy in MF preclinical models, exhibiting in vitro
activity at clinically relevant concentrations. Importantly, the
combination of MEN1703 with the standard of care, RUX, exhibited
synergistic effects, and molecular analyses confirmed the
inhibition of downstream targets of PIM. The results support the
therapeutic potential and relevance of MEN1703 in the treatment
strategies for myelofibrosis.
All abstracts are now available online and can be obtained from
the conference site:
https://www.aacr.org/
About Ryvu Therapeutics
Ryvu Therapeutics is a clinical-stage drug discovery and
development company focused on novel small-molecule therapies that
address emerging targets in oncology. Internally discovered
pipeline candidates use diverse therapeutic mechanisms driven by
emerging knowledge of cancer biology, including small molecules
directed at kinase, synthetic lethality, and immuno-oncology
targets.
Ryvu's most advanced programs include RVU120, a selective
CDK8/CDK19 kinase inhibitor with the potential to treat
hematological malignancies and solid tumors, currently in Phase II
development (i) as a monotherapy for the treatment of patients
with relapsed/refractory acute myeloid leukemia (r/r AML) and
high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in
combination with venetoclax for the treatment of patients with r/r
AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3
kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics
has signed multiple partnering and licensing deals with global
companies, including BioNTech and Exelixis.
The Company was founded in 2007 and is headquartered in Kraków,
Poland. Ryvu is listed on the
Warsaw Stock Exchange and is a component of the mWIG40 index. For
more information, please see www.ryvu.com.
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SOURCE Ryvu Therapeutics