- The nomination of novel Lp-PLA2
inhibitor DPT0415 for the treatment of DR & DME.
- DPT0415 is a highly potent,
selective and safe Lp-PLA2 inhibitor with sufficient target
engagement at a dose of 0.3 mpk and robust efficacy in the
STZ-induced rat DR model.
- This project further validates the
capabilities of DP Technology's drug design platform
RiDYMO.
BEIJING, July 8, 2024
/PRNewswire/ -- DP Technology, an "AI for Science"
paradigm-driven company, today announced the nomination of DPT0415,
a novel small molecule targeting Lipoprotein‐associated
phospholipase A2 (Lp-PLA2), as a preclinical candidate compound for
the treatment of diabetic retinopathy (DR) and diabetic macular
edema (DME).
Lp‐PLA2 belongs to group VII of the PLA2 superfamily, primarily
secreted by macrophages and circulates in the blood as a complex
with low‐density lipoprotein (LDL) and high‐density lipoprotein
(HDL)[1]. Lp-PLA2 hydrolyzes oxidized phospholipids,
typically on low-density lipoprotein (LDL) to generate
lysophosphatidylcholine (lysoPC). LysoPC induces vascular
inflammation, leading to damage to the blood-retinal barrier
(BRB)[2].
DR is a microvascular complication of diabetes and a major cause
of vision loss in middle-aged and elderly people. One-third of
people with diabetes have DR[3]. DME can occur at any
stage of DR, which is caused by excess fluid and lipid accumulation
in the macula due to a breakdown in the blood-retinal barrier. When
the edema extends into the fovea, the patient becomes symptomatic
with metamorphopsia and vision loss[4].
The advent of intraocular anti-vascular endothelial growth
factor (anti-VEGF) drugs has revolutionized the treatment of DME.
However, many patients with DME do not show complete resolution of
fluid despite multiple injections[5], probably because
DR is also an inflammatory disease with many cytokines and
chemokines involved in the process[6]. Thus, the
molecular mechanisms beyond VEGF should be explored. As a Lp-PLA2
inhibitor, oral administration of Darapladib modestly reduced edema
and improved vision in a center-involved DME phase IIa
study[7].
DPT0415 is a highly potent, selective and safe Lp-PLA2
inhibitor with a novel scaffold. It demonstrated sufficient target
engagement at 0.3 mpk, and resecured retinopathy in the STZ-induced
rat DR model. The compound exhibits higher potency, better ADME and
physicochemical properties than Darapladib, and demonstrated
sufficient safety margin in preclinical studies.
"The current standard of care for DME requires eye injections of
VEGF antibody to preserve vision. Due to the invasive route of
administration, patients tend to delay treatment until the later
stages of the disease." said Xiaomin
Zhang, Head of Drug Discovery at DP Technology. "As an
oral therapy for the treatment of DR & DME, DPT0415 may address
inflammation and vascular leakage to improve vision by targeting
Lp-PLA2. Furthermore, the Lp-PLA2 inhibitor DPT0415 has the
potential to substantially change the therapeutic paradigm by
treating DR at an earlier stage to achieve better outcomes."
"DP Technology is the pioneer of the AI for Science paradigm,
dedicated to integrating 'AI + Simulation + Experiments' to address
unmet medical needs," said Weijie
Sun, Founder and CEO of DP Technology. "The successful
discovery of DPT0415 is empowered by multiple modules such as
Uni-FEP and Uni-QSAR in the RiDYMO® platform to optimize potency
and ADME properties. These practical applications of algorithms
represent an important step towards realizing the vision of AI for
Science. We look forward to collaborating with seasoned partners to
advance this program to the next milestone."
The RiDYMO® drug design platform integrates various AI and
physical algorithms, dedicated to the development of drugs for
"undruggable" targets and "best-in-class" molecules. As one of its
core algorithms, Reinforced Dynamics (RiD) has a significant
advantage in the sampling efficiency of molecular dynamics
simulation. By fully leveraging the high-dimensional representation
capabilities of neural networks, RiD can efficiently capture
dynamic conformational changes in complicated biomolecular
systems.
The RiDYMO® platform is dedicated to studying the dynamics of
biological systems and revealing cryptic binding sites,
encompassing a range of challenging systems including
protein-protein interactions (PPIs), intrinsically disordered
proteins (IDPs), membrane proteins, RNA, and others. Its
effectiveness has been confirmed through validation on challenging
targets, including the c-Myc protein, c-Myc RNA, GPX4 protein,
Kv1.3 protein, and others.
About DP Technology
DP Technology, an "AI for Science" new paradigm-driven company,
dedicated to applying Artificial Intelligence and Molecular
Simulation algorithms to solve important scientific problems by
combining advanced computational methods.
Relying on DP Technology's Dynamics-based drug design platform,
RiDYMO®, we have set up a world-leading hit discovery platform. The
team has established external collaborations and built up strong
internal pipeline, focusing on three areas of CNS, oncology and
autoimmune diseases.
For collaboration and further information，please contact Dr.
Xiaomin Zhang, zhangxm@dp.tech.
References:
1. Curr. Pharm. Des. 20, 6256-6269
(2014).
2. Arterioscler. Thromb. Vasc. Biol. 25, 923-931 (2005).
3. Diabetes Care 35, 556-564 (2012).
4. Ophthalmology 122, 1375-1394 (2015).
5. Ophthalmology 117, 1064-1077 (2010).
6. Semin. Immunopathol. 30, 65-84 (2008).
7. Ophthalmology 122, 990-996 (2015).
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SOURCE DP Technology