BEIJING, July 8, 2024 /PRNewswire/ -- DP Technology, an "AI for Science" paradigm-driven company, today announced the nomination of DPT0416, a novel CNS penetrable small molecule targeting Lp-PLA2, as a preclinical candidate for the treatment of Alzheimer's disease (AD).
AD is the most frequent cause of dementia (60%~70%), affecting approximately 57 million people worldwide. Neurovascular dysfunction is an early and predominant event in AD development, independent of classic amyloid pathology. Lp-PLA2 is a phospholipase secreted primarily by inflammatory cells, including peripheral macrophages and CNS microglia. It hydrolyzes oxidized phospholipids typically on low-density lipoprotein (LDL), producing lysophosphatidylcholine (lysoPC) and other potent proinflammatory factors. LysoPC is a key inflammatory mediator on vascular endothelial cells, causing vascular pathology including vessel leakage and BBB damage. The inhibition of Lp-PLA2 by Rilapladib significantly slowed down AD progression and repaired BBB damage in a Phase IIa trial.
DPT0416 is a novel CNS-penetrable Lp-PLA2 inhibitor, exhibiting higher potency, better ADME and physicochemical properties than Rilapladib. In animal models, DPT0416 showed improvement in BBB integrity and a reduction in brain inflammation. The IND-enabling studies are ongoing.
"Alzheimer's disease imposes increasing burdens on the world. Approvals of three anti-amyloid β (Aβ) antibodies mark a pivotal moment in the fight against AD, but the modest clinical efficacy and side effects highlight the complexity of AD and call for more novel interventions with better efficacy. The future treatment of AD should address multiple aspects of the disease, including anti-oxidants, anti-inflammation, and enhancing brain resilience, among others," said Xiaomin Zhang, Head of Drug Discovery at DP Technology. "Targeting Lp-PLA2 is a novel therapy that addresses multiple factors beyond amyloid. Given rilapladib's positive clinical results, the better molecule DPT0416 is expected to bring more benefits to AD and dementia patients."
"DP Technology is revolutionizing the AI for Science landscape by integrating 'AI + Simulation + Experiments' into our processes to address significant medical needs," said Weijie Sun, Founder and CEO of DP Technology. "The successful identification of DPT0416 highlights the power of our RiDYMO® platform, particularly the contributions of the Uni-FEP and Uni-QSAR modules in enhancing molecular interactions, drug-like characteristics, and BBB penetration. These real-world applications of our cutting-edge algorithms signify an important progression towards our envisioned future. We look forward to forging partnerships with trusted collaborators to advance this initiative to the next pivotal stage."
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] Alzheimers. Dement. 17(Suppl 10), e051496 (2021).
[2] Nat. Med. 25, 270-276 (2019).
[3] Med. Res. Rev. 40, 79-134 (2020).
[4] Alzheimers. Dement. 1, 131-140 (2015).
[5] Diab. Vasc. Dis. Res. 14, 200-213 (2017).
![Fig. 1 Crystal structure of GPX4 protein in complex with ML162[3] (PDB ID: 6HKQ) and existing covalent inhibitors.](https://mma.prnasia.com/media2/2473521/image_5027215_10170451.jpg?p=medium600)
