作者: Cheng, Maosheng ; Li, Jiabo ; Li, Jianheng ; Yang, Huali ; Zhang, Yaming ; Lian, Wenxiong ; Wang, Zhijian ; Cai, Qingkui ; Song, Pengfei ; Wang, Hanxun

Due to the unclear selectivity of the protein system, designing selective small molecule inhibitors has been a significant challenge. This issue is particularly prominent in the phosphodiesterases (PDEs) system. Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10 A (PDE10A) are two closely related subtypes of PDE proteins that play diverse roles in the immune system and tumorigenesis, respectively. Distinguishing the selective mechanism of these two subtypes is crucial for maximizing therapeutic efficacy and minimizing the side effects of inhibitors. We have investigated the interactions between crucial amino acid residues and selective inhibitors through several computer-aided drug design methods such as molecular docking, molecular dynamic simulation, MM/GBSA calculation, and alanine scanning mutagenesis revealing the selective inhibition mechanism between PDE1B and PDE10A. Our finding shows the selective residues of PDE1B are His373 and Gln421, while the selective residues for PDE10A are Tyr683 and Phe719. Specifically, PDE10A inhibitors form hydrogen bonds and hydrophobic interactions with Tyr683 and Phe719, whereas PDE1B inhibitors only demonstrate weak hydrophobic interactions in the corresponding region. Overall, elucidating the selectivity mechanism underlying the differential interaction between PDE1B and PDE10A is crucial for designing inhibitors with distinct selectivity towards PDE1B/10 A.

2025-02-01·ANESTHESIOLOGY

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice

Article

作者: Kallenborn-Gerhardt, Wiebke ; Gerninghaus, Hannah ; Hernandez-Olmos, Victor ; Petersen, Jonas ; Schmidtko, Achim ; Feil, Susanne ; Sinderwald, Rekia ; Stehle, Daniel ; Proschak, Ewgenij ; Duman, Emre ; Feil, Robert ; Lu, Ruirui ; Nagel, Chantal ; Metzner, Katharina ; Gross, Tilman ; Zhou, Fangyuan

Background::

Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform phosphodiesterase 10A (PDE10A) might be a target for analgesic therapy.

Methods::

In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.

Results::

PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD, 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (two-way ANOVA, group, F[1,18] = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund’s adjuvant (F[1,14] = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.

Conclusions::

Collectively, the data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

2025-02-01·REPRODUCTION

Potent and sustained enhancement of human sperm motility using novel cyclic AMP up-regulators

Article

作者: Otero, Patricia ; Marín-Briggiler, Clara I ; Ferrulli, Mariana ; Oscoz Susino, Natalia ; Minotti, Florencia ; Buffone, Mariano G ; Luque, Guillermina M ; Lavolpe, Mariano ; Krapf, Dario

Cyclic adenosine monophosphate (cAMP) plays a central role in sperm physiology. Various cAMP up-regulators, both cAMP analogs and phosphodiesterase (PDE) inhibitors, have been used in handling human sperm in vitro, though conflicting results and variable responses among patients have been reported. This study aims to evaluate the ability of two compounds - Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3’-5’-cyclic monophosphothioate (cBiMPs), a cAMP analog, and TAK-063, a specific PDE10A inhibitor - to enhance human sperm motility parameters and, consequently, improve sperm preparation procedures. Our results showed that both cBiMPs and TAK-063 significantly enhanced human sperm motility and hyperactivation compared to the control (dimethyl sulphoxide (DMSO)). They also increased protein phosphorylation levels without inducing premature acrosomal exocytosis or DNA fragmentation. The enhancement of sperm motility persisted for 4 h after their removal, surpassing the effects of known cAMP analogs (8-bromo-adenosine-3’, 5’-cAMP (8-Br-cAMP) or dibutyryl cAMP (db-cAMP)) or PDE inhibitors (3-isobutyl-1-methylxanthine (IBMX) or pentoxifylline (PTX)). Furthermore, the presence of cBiMPs or TAK-063 during sperm selection resulted in higher recovery rates in comparison to the control, and these compounds effectively improved sperm motion in both fresh and cryopreserved samples with impaired motility. In conclusion, cBiMPs and TAK-063 exhibit potent and sustained effects on human sperm motility, enhancing the efficiency of sperm preparation techniques. The ability to improve sperm motility holds significant implications for male infertility treatment, facilitating the use of low complexity techniques such as intrauterine insemination or in vitro fertilization, and may also aid in selecting viable testicular sperm for intracytoplasmic sperm injection.

项与 PDE10A inhibitors(Janssen) 相关的新闻（医药）

2024-12-11

·Endpoints

BenevolentAI restructures; Cimeio, Kyowa ink cell therapy deal

Plus, news about NewAmsterdam, Rocket, ImmunityBio, CG Oncology, Spruce Biosciences, Pharming, Veradermics, Noema Pharma, Ambrosia Biosciences, EsoBiotec, Cellectar Biosciences and Hepion: BenevolentAI’s overhaul: The struggling AI biotech said it plans to lay off staff, consider delisting from the Euronext Amsterdam stock exchange, partner its early-stage assets and undergo other additional organizational shifts as co-founder Ken Mulvany returns . Its Amsterdam-listed stock was down 10% on Wednesday. — Kyle LaHucik Cimeio Therapeutics, Kyowa Kirin make a deal: The Japanese drugmaker is paying up to $300 million as part of an agreement to develop new cell therapies. Additional financial terms were not disclosed. — Jaimy Lee At least three public offerings have been disclosed over the past day, including NewAmsterdam ’s bid to raise $300 million; Rocket ’s upsized $165 million offering ; ImmunityBio ’s $100 million financing ; and CG Oncology ’s offering , which has yet to be priced. — Jaimy Lee Spruce’s Phase 2b fail for endocrine disorder drug: The South San Francisco biotech said tildacerfont administered once daily did not meet the primary endpoint of glucocorticoid reduction in a mid-stage study of people with adult congenital adrenal hyperplasia. But the trial’s principal investigator said the data suggest twice daily dosing may be more effective. Its stock $SPRB was down about 25% on Wednesday morning. — Ayisha Sharma Pharming’s rare disease med passes Phase 3 test in kids: The Dutch drugmaker’s Joenja for activated phosphoinositide 3-kinase delta syndrome (APDS) met the primary endpoints in a late-stage trial of patients aged four to 11 years old. Joenja won FDA approval for APDS patients aged 12 and older in March 2023. Pharming plans to submit global regulatory filings in children starting in 2025. — Ayisha Sharma Veradermics’ $75M Series B: The Connecticut-based dermatology and aesthetics biotech raised the financing as it begins a Phase 2/3 study in hair loss. — Kyle LaHucik Noema adds $35M from EQT Life Sciences: A second close of a Series B first announced in March of last year brings the total for the round to CHF 130 million, which is about $147 million. The cash will fund Noema’s four ongoing Phase 2 trials: mGluR5 negative allosteric modulator basimglurant in trigeminal neuralgia and seizures in tuberous sclerosis complex; gemlapodect, a PDE10a inhibitor, in Tourette syndrome; and NOE-115, a monoamine modulator, in menopause symptoms. — Elizabeth Cairns Merck backs Ambrosia: The New Jersey pharma giant invested in the biotech’s Series A, which now totals $25 million. Ambrosia previously announced plans to take over a former Pfizer site in Boulder as it builds out an oral small-molecule pipeline for obesity and metabolic disorders. — Kyle LaHucik EsoBiotec scores €22M: The Belgian cell therapy specialist raised the equivalent of $23 million from backers that include Thuja Capital, UCB Ventures and Invivo Partners. The company’s immune-shielded lentiviral vector, which is called ESO-T01, is designed to reprogram T lymphocytes into BCMA CAR-T cells in vivo . It will enter an investigator-initiated trial in multiple myeloma in China, its first in humans, and data are expected in the second half of 2025, which could allow expansion to indications including autoimmune diseases. — Elizabeth Cairns Cellectar lays off 60% of its workers: The biotech is prioritizing its pipeline and letting go of staff. Cellectar had 20 employees at the end of 2023. Its stock price $CLRB sank 62% in pre-market trading on Wednesday. — Kyle LaHucik Hepion Pharmaceuticals ends merger plans with Pharma Two B. — Jaimy Lee

细胞疗法临床3期临床2期上市批准临床结果

2024-12-11

·PRNewswire

EQT Life Sciences Leads Series B Extension in Noema Pharma, Raising Total Series B Financing to CHF 130 million

Proceeds will be used to enable key late-stage clinical trial readouts for assets across several underserved neurological diseases with high unmet medical need. EQT Life Sciences has led the extension, and joins a consortium of prominent global biotechnology investors. The investment builds on EQT Life Sciences' previous successful partnership with neurology-focused repeat entrepreneur and Noema Pharma CEO Ilise Lombardo, MD STOCKHOLM, Dec. 11, 2024 /PRNewswire/ -- EQT Life Sciences is pleased to announce that the LSP 7 fund has invested in Noema Pharma ("the Company"). The clinical-stage biotech company headquartered in Basel, Switzerland is developing a pipeline of first-in-disease therapeutics that address central nervous system (CNS) disorders. The Series B extension brings the total capital raised in the round to CHF 130 million, including prior investments from Forbion, Jeito Capital, Sofinnova Partners, Gilde Healthcare, Polaris Partners, Invus and UPMC Enterprises. CNS disorders are a significant area of unmet medical need, affecting hundreds of millions of people worldwide who often face inadequate treatment options with limited effectiveness and significant side effects. Many of the conditions targeted by Noema Pharma have historically been difficult to treat due to their complex nature and the lack of effective therapies. By leveraging its diverse portfolio of neurological assets and innovative clinical pipeline, Noema Pharma is strongly positioned to address these debilitating disorders and provide much-needed hope and transformative solutions to patients living with these life-altering challenges. The Company's portfolio includes four active Phase 2 trials, with key readouts from all studies anticipated in 2025. Proceeds from the financing will drive the continued development of Noema Pharma's clinical-stage assets, including its lead candidate basimglurant (NOE-101), a mGluR5 inhibitor currently in Phase 2 trials for severe pain in trigeminal neuralgia (TN) and seizures in tuberous sclerosis complex (TSC). Additionally, the Company is advancing gemlapodect (NOE-105), a PDE10a inhibitor in Phase 2 for Tourette syndrome and childhood onset fluency disorder (COFD or stuttering), as well as NOE-115, a broad-spectrum monoamine modulator in a Phase 2 trial for vasomotor symptoms and additional symptoms of menopause. Ilise Lombardo, MD, CEO of Noema Pharma, stated: "We are thrilled to welcome EQT Life Sciences as a lead investor and to have Felice join our Board. Their support and expertise will be invaluable as we progress our clinical programs and strive to make a meaningful impact on patients' lives." Felice Verduyn-van Weegen, Partner at EQT who is joining the Company's Board of Directors, commented: "Noema Pharma's innovative approach to CNS disorders aligns very well with our investment strategy and we are excited to support their late-stage clinical pipeline and transformative therapies. Having worked with Ilise Lombardo on a previous successful investment, her exceptional leadership as a repeat entrepreneur further reinforces our confidence in Noema's potential to deliver meaningful impact to patients in need." Contact EQT Press Office, [email protected] This information was brought to you by Cision The following files are available for download: WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床2期

2024-12-11

·Business Wire

Noema Pharma extends Series B financing round, closing at CHF 130 Million ($147 Million)

BASEL, Switzerland--( BUSINESS WIRE )-- Noema Pharma , a clinical-stage biotech company targeting debilitating central nervous system (CNS) disorders, announced the successful close of a Series B extension financing round with an investment from EQT Life Sciences, bringing the total capital raised in the round to CHF 130 million (approx. USD 147 million). With its investment in Noema Pharma, EQT Life Sciences joins the syndicate of previous Series B investors including Forbion, Jeito Capital, Sofinnova Partners, Gilde Healthcare, Polaris Partners, Invus and UPMC Enterprises. The new financing will support Noema Pharma’s four active Phase 2 trials, with key data readouts anticipated in 2025. This includes additional development activities for basimglurant (NOE-101), an mGluR5 negative allosteric modulator currently in Phase 2 trials for severe pain in trigeminal neuralgia (TN) and seizures in tuberous sclerosis complex (TSC); gemlapodect (NOE-105), a PDE10a inhibitor in a Phase 2b trial for Tourette syndrome and under development for childhood-onset fluency disorder (COFD or stuttering); and NOE-115, a broad-spectrum monoamine modulator in a Phase 2 trial for vasomotor symptoms and other symptoms of menopause. Ilise Lombardo, MD, CEO of Noema Pharma, stated: " This latest financing underscores the strong support and confidence from investors in Noema’s vision to treat neuroscience-based conditions. We are thrilled to welcome EQT Life Sciences into this strong syndicate of investors and have Felice join our Board. EQT’s support and expertise alongside our syndicate of investors will be invaluable as we progress our clinical programs and strive to make a meaningful impact on patients' lives." Felice Verduyn-van Weegen , Partner at EQT and member of the Board at Noema, commented: " Noema Pharma's innovative approach to CNS disorders aligns very well with our investment strategy and we are excited to support their late-stage clinical pipeline and transformative therapies. Having worked with Ilise Lombardo on a previous successful investment, her exceptional leadership as a repeat entrepreneur reinforces our confidence in Noema's potential to deliver meaningful impact to patients in need.” The Series B extension follows the initial Series B financing of CHF 103 million (USD 112 million) announced on March 2023, and a CHF 54 million (approx. USD 60 million) Series A round in December 2020. Noema Pharma was founded in 2019 with seed investment from Sofinnova Partners. Notes to Editors About Noema Pharma Noema Pharma is a clinical-stage biotech company advancing a portfolio of transformative, first-in-disease therapeutics targeting neuroscience-based conditions with high unmet need. Noema has four programs currently in active Phase 2 clinical trials evaluating seizures in Tuberous Sclerosis Complex, pain in Trigeminal Neuralgia, Tourette syndrome and vasomotor symptoms plus CNS-mediated symptoms of menopause with readouts expected in 2025. Noema was founded by leading venture capital firm Sofinnova Partners and is supported by current investors including Forbion, Gilde Healthcare, Invus, Jeito Capital, Polaris Partners and UPMC Enterprises. Learn more at www.noemapharma.com . About EQT Life Sciences EQT Life Sciences was formed in 2022 following the integration of LSP, a leading European life sciences venture capital firm, into the EQT platform. As LSP, the firm raised over EUR 3.0 billion and supported the growth of more than 150 companies since it started to invest over 30 years ago. With a dedicated team of highly experienced investment professionals coming from backgrounds in medicine, science, business, and finance, EQT Life Sciences backs entrepreneurs who have ideas that could truly make a difference for patients. The team combines deep sector knowledge, analytical skills, and investment experience to provide the added value that entrepreneurs seek. For more information, go to eqtgroup.com/private-capital/life-sciences/

临床2期

100 项与 PDE10A inhibitors(Janssen) 相关的药物交易

登录后查看更多信息