GPX4

Research on ferroptosis is gaining momentum, but the development of small molecule inhibitors faces numerous challenges BEIJING, Aug. 1, 2024 /PRNewswire/ -- Glutathione peroxidase 4 (GPX4) is recognized as a critical regulator of ferroptosis, playing a significant role in lipid and amino acid metabolism, as well as influencing cellular aging, oncogenesis, and cell death [1]. Targeting GPX4-mediated ferroptosis presents a promising therapeutic strategy, particularly in the treatment of cancer [2]. Continue Reading Fig. 1 Crystal structure of GPX4 protein in complex with ML162[3] (PDB ID: 6HKQ) and existing covalent inhibitors. Fig. 2 Enhanced Sampling of GPX4 Protein with RiD Fig. 3 Molecular dynamics simulations combined with the organic solvent probe to induce the discovery of a new pocket in GPX4. Fig. 4 Results of ML162 and screened molecules in GPX4 enzymatic assay (A), SPR assay (B), and ROS assay (C) Fig. 5 The workflow of identifying novel non-covalent hits against GPX4 using the RiDYMO® Reinforced Dynamics Platform

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). Continue Reading 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 ([email protected]). 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). SOURCE DP Technology

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). Continue Reading 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, [email protected]. 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). SOURCE DP Technology