作者: Casarini, Dulce E ; Cárdenas, Pilar ; Lorca, Ramón A ; Céspedes, Carlos ; Nuñez-Allimant, Camila ; Cid-Salinas, Catalina ; Prieto, Minolfa C ; Vallotton, Zoe ; Silva, Katherin ; Oliveira, Lilian Caroline Gonçalves de ; León, Allison C ; Gonzalez, Alexis A

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1^-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.

2024-07-01·CNS Neuroscience & Therapeutics

Activation of GPER1 by G1 prevents PTSD‐like behaviors in mice: Illustrating the mechanisms from BDNF/TrkB to mitochondria and synaptic connection

Article

作者: Chen, Lixia ; Wang, Jingji ; Zhang, Zhengrong ; Zhu, Guoqi ; Wang, Zisheng ; Zhang, Yang ; Yang, Shaojie

AbstractBackgroundG1 is a specific agonist of G protein‐coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post‐traumatic stress disorder (PTSD) and its mechanisms are unclear.ObjectiveTo evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain‐derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling.MethodsThis study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD‐like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively.ResultsThe expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD‐like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria‐related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA‐12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD‐like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively.ConclusionG1 improved PTSD‐like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.

2023-11-01·Steroids

Mining the ZINC database of natural products for specific, testosterone-like, OXER1 antagonists

Article

作者: Panagiotopoulos, Athanasios A ; Castanas, Elias ; Konstantinou, Evangelia ; Pirintsos, Stergios A ; Kampa, Marilena

OXER1, the receptor for the oxidized arachidonic acid metabolite 5-oxo-ETE has been reported to play a significant role in inflammatory responses, being responsible for leucocyte chemotactic responses. Recently, we have identified OXER1 (GPR170) as a membrane receptor for androgens in prostate and breast cancer cells. Testosterone action via OXER1 induces specific Ca²⁺ release from intracellular organelles, modifies polymerized actin distribution induces apoptosis and decreases cancer cell migration. These actions are antagonized by 5-oxo-ETE. In addition, 5-oxo-ETE through a G_αi protein decreases cAMP, an action antagonized by testosterone. In this work, we mined the ZINC15 database, using QSAR, for natural compounds able to signal through G_αi and G_βγ simultaneously, mimicking testosterone actions, as well as for specific G_βγ interactors, inhibiting 5-oxo-ETE tumor promoting actions. We were able to identify four druggable G_αβγ and seven G_βγ specific OXER1 interactors. We further confirmed by bio-informatic methods their binding to the 5-oxo-ETE/testosterone binding groove of the receptor, their ADME properties and their possible interaction with other receptor and/or enzyme targets. Two compounds, ZINC04017374 (Naphthofluorescein) and ZINC08589130 (Puertogaline A) were purchased, tested in vitro and confirmed their OXER1 G_βγ and G_αβγ activity, respectively. The methodology followed is useful for a better understanding of the mechanism by which OXER1 mediates its actions, it has the potential to provide structural insights, in order to design small molecular specific interactors and ultimately design new anti-inflammatory and anti-cancer agents. Finally, the methodology may also be useful for identifying specific agonists/antagonists of other GPCRs.

项与 OXER1 Antagonist(Liminal BioSciences Ltd.) 相关的新闻（医药）

2023-08-08

·PRNewswire

Liminal BioSciences Reports Second Quarter Financial Results 2023

Provided R&D update on GPCR-targeted pipeline, including nomination of lead candidate for OXER1 antagonist program Closed June 30, 2023 with over CAD 19 million cash on hand, expecting to provide cash runway into December 2023 Net loss from continuing operations of CAD 9 million during the quarter ended June, 2023 compared to CAD 6.4 million during the second quarter of 2022 Entry into Arrangement Agreement with Structured Alpha LP potentially providing minority shareholders US$8.50 in cash per Common Share LAVAL, QC and CAMBRIDGE, England, Aug. 8, 2023 /PRNewswire/ - Liminal BioSciences Inc. (Nasdaq: LMNL) ("Liminal BioSciences" or the "Company"), a development-stage biopharmaceutical company focused on discovering and developing distinctive novel small molecule therapeutics for metabolic, inflammatory, and fibrotic diseases, today reported its financial results for the second quarter ended June 30, 2023. "I am very pleased with the progress we have made in the past quarter, marking a significant leap forward in our mission to develop novel treatments for metabolic, fibrotic and inflammatory conditions," stated Bruce Pritchard, Chief Executive Officer of Liminal BioSciences. "Our dedication to innovation and scientific excellence has led to several key milestones, bringing us closer to clinical studies in which we aim to seek early biological validation of our assets." Recent R&D milestones LMNL6326 was nominated as the lead preclinical candidate for our OXER1 antagonist development program, targeting the treatment of eosinophil-driven diseases. Advancement of clinical trial application (CTA) enabling preclinical studies of LMNL6511 to support CTA filing for Phase 1 clinical trial in H2 2023. Insights gained from In Vivo preclinical studies of LMNL6511 to further refine potential indications' spectrum. GPR40 agonist development program on track and the Company aims to identify potent, low molecular weight GPR40 agonists without significant PPARy activity in 2023. Upcoming R&D Milestones GPR84 antagonist program On-going In-vivo experiments expected to narrow down selection of a lead clinical indication in 2023. Ongoing Clinical Trial Application (CTA)-enabling studies for first-in-human clinical trial in 2023. Expect to file CTA for first in-human Phase 1 clinical trial and to commence clinical trial in H2 2023. OXER1 antagonist program Aim to file CTA/Investigational New Drug (IND) for LMNL6326 first-in-human clinical trial in 2024. GPR40 antagonist program Aim to identify potent, low molecular weight GPR40 agonists without significant PPARγ activity in 2023. Arrangement with SALP On July 11, 2023, we entered into a definitive arrangement agreement (the "Arrangement Agreement") with Structured Alpha LP ("SALP") under which SALP will acquire all of the issued and outstanding common shares of Liminal BioSciences (the "Common Shares") that it does not already own, subject to customary closing conditions. The transaction will be implemented by way of plan of arrangement under the Canada Business Corporations Act. Under the terms of the Arrangement Agreement, Liminal BioSciences shareholders (other than SALP and its affiliates or associates) will receive US$8.50 in cash per Common Share. Liminal BioSciences intends to mail a management information circular to its shareholders in the coming weeks for the special meeting of shareholders anticipated to be held virtually on September 15, 2023 to approve the proposed transaction. The transaction is expected to close no later than September 30, 2023, subject to satisfaction of customary closing conditions. The transaction is not subject to any financing condition. Second Quarter Ended June 30th 2023 Financial Results All figures presented in this section are in Canadian dollars. Cash and cash equivalents were $19.3 million at June 30, 2023 while our working capital, i.e., the current assets net of current liabilities, was $16.4 million. Research and development expenses were $4.3 million during the second quarter of 2023 compared to $3.9 million for the second quarter of 2022. The increase of $0.4 million in R&D expenses during the quarter ended June 30, 2023 compared to the corresponding period in 2022 was mainly attributable to an increase of $0.7 million in preclinical studies expense associated with the advancement of our GPR84 and OXER1 antagonist programs. This increase was partially offset by a $0.3 million decrease in personnel costs due to reductions in our workforce. Administration expenses were $4.8 million for the second quarter of 2023 compared to $4.5 million for the second quarter of 2022. The decrease of $0.3 million in administration expenses during the quarter ended June 30, 2023 compared to the corresponding period in 2022 was mainly attributable to an increase of $0.9 million in professional fees incurred in connection with the non-binding proposal received from SALP, which was partially offset by a $0.6 million decrease in reduced directors' and officers' insurance premiums. Net loss from continuing operations, net of taxes was $9.0 million for the second quarter of 2023 compared to $6.3 million for the second quarter of 2022. This decrease of $2.6 million was mainly driven by the decrease in foreign exchange gains of $1.7 million, a decrease in the gains from the change in fair value of the warrant liability that is measured at FVPL of $1.3 million, an increase in administration expenses of $0.3 million reflecting the increase in professional fees and an increase in R&D expenses of $0.4 million as a result of an increase in preclinical studies expense associated with the advancement of our GPR84 and OXER1 antagonist programs. These increases in expenses were partially offset by a $1.0 million decrease in finance costs. Total loss from discontinued operations Total loss from discontinued operations was $0.2 million during the quarter ended June 30, 2023 compared to a total income from discontinued operations of $0.1 million during the corresponding period in 2022. This variation was mainly attributable to to changes in the underlying assumptions used to value the provision pertaining to the CDMO. Net Loss was $9.1 million for the second quarter of 2023 compared to $6.2 million for the second quarter of 2022. This increase in the net loss was mainly driven by the decrease in foreign exchange gains of $1.7 million, a decrease in the gains from the change in fair value of the warrant liability that is measured at FVPL of $1.3 million, an increase in administration expenses of $0.3 million reflecting the increase in professional fees and an increase in R&D expenses of $0.4 million as a result of an increase in preclinical studies expense associated with the advancement of our GPR84 and OXER1 antagonist programs. These increases in expenses were partially offset by a $1.0 million decrease in finance costs. About Liminal BioSciences Inc. Liminal BioSciences is a development-stage biopharmaceutical company focused on discovering and developing novel and distinctive small molecule therapeutics that modulate G protein-coupled receptor pathways (GPCRs). The Company is designing proprietary novel small molecule therapeutic candidates with the intent of developing best/first in class therapeutics for the treatment of metabolic, inflammatory and fibrotic diseases with significant unmet medical needs, using its integrated drug discovery platform, medicinal chemistry expertise and deep understanding of GPCR biology. The Company's pipeline is currently made up of three programs. LMNL6511, a selective antagonist for the GPR84 receptor, is expected to commence a Phase 1 clinical trial in the second half of 2023. LMNL6326 has been nominated as the preclinical candidate for its OXER1 antagonist program, and the Company is also developing GPR40 agonists. Both the OXER1 antagonist program and GPR40 agonist program are currently in the preclinical stage. In addition to these programs, the Company continues to explore other development opportunities to add to its pipeline. Liminal BioSciences has active business operations in Canada and the United Kingdom. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Some of the forward-looking statements can be identified by the use of forward-looking words. Statements that are not historical in nature, including the words "anticipate," "expect," "suggest," "plan," "believe," "intend," "estimate," "target," "project," "should," "could," "would," "may," "will," "forecast" and other similar expressions are intended to identify forward-looking statements. These statements include those related to Liminal BioSciences' objectives, strategies and businesses that involve risks and uncertainties. Forward–looking information includes statements concerning, among other things: advancement of Liminal Biosciences' candidates or development programs, including the timing and outcome of the potential development of the Company's R&D programs such as the development of LMNL6511, LMNL6326 and our GPR40 agonist discovery program; the timing of initiation or nature of preclinical and clinical trials, including the expected commencement of a Phase 1 clinical trial of LMNL6511 in the second half of 2023; the contemplated potential therapeutic areas, including Eosinophilic mediated diseases and T2D; the potential for our development programs to address significant unmet medical needs; our ability to add new development opportunities to our pipeline; our ability to continue to comply with Nasdaq Listing Rule 5450(a)(1) to remain listed on the Nasdaq Capital Market; the ability to complete and the timing of completion of the transactions contemplated by the arrangement agreement between Liminal BioSciences and SALP, including the parties' ability to satisfy the conditions to the consummation of the transaction and the possibility of any termination of the agreement; our expected cash runway and our ability to actively seek and close on opportunities to monetize non-core assets or commercial opportunities related to our assets. These statements are "forward-looking" because they are based on our current expectations about the markets we operate in and on various estimates and assumptions. Actual events or results may differ materially from those anticipated in these forward-looking statements if known or unknown risks affect our business, or if our estimates or assumptions turn out to be inaccurate. Among the factors that could cause actual results to differ materially from those described or projected herein include, but are not limited to, risks associated with: the Company's ability to develop, manufacture, and successfully commercialize product candidates, if ever; the impact of current global economic conditions and other geopolitical tensions on the Company's workforce, business operations, clinical development, regulatory activities and financial and other corporate impacts; the availability of funds and resources to pursue R&D projects, clinical development, manufacturing operations or commercialization opportunities; the successful and timely initiation or completion of preclinical and clinical trials; the ability to take advantage of financing opportunities or business opportunities in the pharmaceutical industry, uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals; our ability to comply with Nasdaq listing rules and remain listed on the Nasdaq Capital Market and general changes in economic conditions, including as a result of increased inflation, bank failures and rising interest rates. You will find a more detailed assessment of these risks, uncertainties and other risks that could cause actual events or results to materially differ from our current expectations in the filings and reports the Company makes with the U.S. Securities and Exchange Commission and Canadian Securities Administrators, including in the Annual Report on Form 20-F for the year ended December 31, 2022, as well as other filings and reports Liminal Biosciences' may make from time to time. As a result, we cannot guarantee that any given forward-looking statement will materialize. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements and estimates, which speak only as of the date hereof. We assume no obligation to update any forward-looking statement contained in this press release even if new information becomes available, as a result of future events or for any other reason, unless required by applicable securities laws and regulations. SOURCE Liminal BioSciences Inc.

临床1期财报引进/卖出

2023-08-01

·FierceBiotech

C4X sells full rights for substance use disorder drug to Indivior as part of refocus

Indivior said the deal is “aligned with our goal to build a strong and balanced pipeline focused on addiction treatments.” Indivior has paid 15.95 million pounds sterling ($20.4 million) to C4X Discovery for the full rights to the British biotech’s orexin-1 receptor antagonist being developed for substance use disorder. The two companies originally signed a deal back in 2018 that saw Indivior pay $10 million upfront and pledge up to $284 million in milestones if the asset, dubbed C4X3256, or a library of additional orexin-1 compounds included in the agreement proved successful. In return for the almost 16 million pound upfront payment today, C4X is surrendering the chance to ever cash in on those milestones. The Manchester, England-based biotech framed the decision as “part of C4XD’s evolution towards becoming an immuno-inflammatory therapeutics company.” “Indivior has made excellent progress with our orexin-1 candidate, and we are proud that they now wish to take this program fully in-house,” C4X Chief Business Officer Bhavna Hunjan said in the Aug. 1 release. “The agreement also provides an opportunity for us to crystallize value for the program early and underpins and accelerates our new strategy.” The company will use today’s funds alongside preclinical milestone payments from an IL-17 inhibitor licensed to Sanofi and a Nrf2 activator licensed to AstraZeneca to “further advance our newly focused portfolio towards and into the clinic.” C4X’s unpartnered portfolio centers around a MALT1 inhibitor, although the biotech said in the release that a partnering process for the asset has now been “initiated.” So far, C4X3256 is the only asset hailing from C4X that has made it into the clinic. The drug began a phase 1 multiple ascending dose trial in 2020, according to ClinicalTrials.gov. For Indivior, getting its hands on the full rights to C4X3256, which has been rechristened INDV-2000, is “aligned with our goal to build a strong and balanced pipeline focused on addiction treatments,” Chief Scientific Officer Christian Heidbreder, Ph.D., said in today’s release. “Importantly, we know the asset well, having worked closely with C4X Discovery for more than five years,” Heidbreder added. “We recognize its exciting potential and will continue to progress it as a novel approach to the treatment of opioid use disorder, as well as more broadly in substance use disorders.” Indivior isn’t the only one who sees potential in the candidate. In 2019, the U.S. National Institutes of Health’s program for opioid misuse and other long-term addictions handed over a $10.6 million grant to Indivior for development of the compound. Orexin regulates arousal, wakefulness and appetite, and focusing in on the neuropeptide has seen some regulatory success for insomnia. Idorsia, for example, secured the approval of its dual orexin receptor antagonist Quviviq as a sleeping pill. However, the Swiss biotech company had less luck trying to pursue a selective orexin-antagonist as a binge-eating disorder treatment, dropping the indication after a phase 2 trial fail.

临床1期临床2期上市批准引进/卖出

2023-07-21

·FierceBiotech

Sleepless nights for 500 Idorsia staff as biotech halves cash burn to outlast weak insomnia drug sales

Most of the up to 500 positions in jeopardy at Idorsia will be located in R&D and related roles. Up to 500 roles at Idorsia are at risk as the Swiss biotech tries to halve its cash burn while it waits for its approved insomnia treatment Quviviq to pay off. Facing a “challenging financial situation” due to “lower than anticipated product sales and a difficult global financial environment,” the company has decided to sacrifice its R&D work in order to “maximize the time the company has to deliver commercial success.” Exactly what will happen is still to be decided. Idorsia will now review its development pipeline and jettison all candidates that can’t be “advanced rapidly and with reasonable financial investment.” Work on those unwanted programs will be either paused or prepared for partnership or out-licensing, the biotech explained in an early morning release Friday. The ultimate goal is to reduce cash burn at the company’s Allschwil, Switzerland, headquarters by 50% by early 2024. It means a worrying period of limbo for many employees. Up to 500 positions could be set to go as part of the “cost reduction initiative,” mostly located in the R&D team and related roles. The affected employees will be decided as part of a consultation process due to wrap up by the end of the year. “I continue to believe that Quviviq can be the success we hope for, but unfortunately it will take longer than originally planned,” the biotech’s CEO Jean-Paul Clozel, M.D., said in the release. “Idorsia’s immediate objective is therefore to maximize the time the company has to deliver commercial success with its products. This means making any funds that are raised last as long as possible by significantly reducing our global cash-burn.” “The cost reduction initiative together with potential collaborations will give the company the time it needs to realize the value we have created,” Clozel added. “I deeply regret having to launch such an initiative, but we simply cannot sustain current investment levels.” While Idorsia has previously claimed that Quviviq has become the No. 1 branded insomnia treatment since Idorisa launched it onto the U.S. market in May 2022, delays in securing reimbursement meant it only brought in total net sales of 4.3 million Swiss francs ($4.9 million) in the first quarter of the 2023. In an earnings report in April, Clozel insisted that when it came to the reimbursement delays, “progress has been made and the situation is steadily improving.” The company ended March with 212 million Swiss francs ($245 million) in cash and equivalents. Since then, Idorsia has secured bridge financing of 75 million Swiss francs ($86 million) as well as sold its Asia-Pacific rights outside of China to Sosei Heptares. If its commercial rollout has been slow, Idorsia hasn’t had much luck in the clinic in recent years, either. In 2021, its Fabry disease medicine lucerastat flamed out in a phase 3 trial, while cenerimod missed the primary goal in a phase 2b systemic lupus erythematosus study. The following year saw its selective orexin-1 antagonist ACT-539313 fail to hit its goal in a binge eating disorder study, prompting the company to give up on the indication. It's made for a tough period for a company that arrived on the biotech scene with a splash in 2017 by way of a spinout from Actelion, which was bought by Johnson & Johnson. Idorsia launched with $1 billion in cash and a handful of clinical-stage drug candidates—plus a potentially lucrative development deal with J&J for the blood pressure medication aprocitentan, which has continued to show potential in a phase 3 trial. Shares in the company have been on a steady decline in 2023, hovering around the 6.30 Swiss franc mark this morning from a January opening price 15.33 Swiss francs.