More than 2000 compounds have been reported from cyanobacteria. The most successful example is dolastatin 10, of which a related compound monomethylauristatin E is used as antibody-drug conjugate (ADC) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Recently genome-based analyses by Piel led to the discovery of novel compounds from cyanobacteria. W. H. Gerwick found a potential as anti-SARS-CoV-2 agent in gallinamide A, which was reported as a cathepsin L inhibitor. In our group columbamides were isolated from the marine cyanobacterium Moorena bouillonii. The geometry of the double bond was determined by the coupling constant obtained using non-decoupled heteronuclear single quantum coherence (HSQC). The configuration of chloromethine in a long-chain acyl moiety was determined by the Ohrui method at room temperature using a chiral HPLC column. Columbamide D showed biosurfactant activity. One strain many compounds (OSMAC) is a method to discover new compounds by changing culture conditions. Prior to our experiments, attempts to apply OSMAC in cyanobacteria resulted in the induction or up-regulation of only known compounds. The heat shock culture of the freshwater cyanobacterium Microcystis aeruginosa up-regulated a ribosomal peptide argicyclamide C. At the same time, we discovered bis-prenylated and monoprenylated argicyclamides A and B. More recently iron-limited culture produced hydroxylated argicyclamide A. OSMAC and genome-based screening could lead the discovery of unique biologically active compounds from cyanobacteria.

2024-01-01·Journal of Neuroscience Research

Blockage of the fractalkine pathway reduces hyperalgesia and prevents morphological glial alterations—Comparison between inflammatory and neuropathic orofacial pain in male rats

Article

作者: da Silva, Cristiane Maria Pereira ; Dias, Diego Bernarde Souza ; Alves, Luiza Clertiani Vieira ; Vale, Mariana Lima ; Gondim, Delane Viana ; Lima‐Júnior, Roberto César Pereira ; Alves, Bruno Wesley de Freitas ; Pereira, Anamaria Falcão ; Lisboa, Mario Roberto Pontes

AbstractThis study aimed to evaluate the effects of inhibitors of the fractalkine pathway in hyperalgesia in inflammatory and neuropathic orofacial pain in male rats and the morphological changes in microglia and satellite glial cells (SGCs). Rats were submitted to zymosan‐induced arthritis of the temporomandibular joint or infraorbital nerve constriction, and treated intrathecally with a P2X7 antagonist, a cathepsin S inhibitor or a p‐38 mitogen‐activated protein kinase (MAPK) inhibitor. Mechanical hyperalgesia was evaluated 4 and 6 h following arthritis induction or 7 and 14 days following nerve ligation. The expression of the receptor CX3CR1, phospho‐p‐38 MAPK, ionized calcium‐binding adapter molecule‐1 (Iba‐1), and glutamine synthetase and the morphological changes in microglia and SGCs were evaluated by confocal microscopy. In both inflammatory and neuropathic models, untreated animals presented a higher expression of CX3CR1 and developed hyperalgesia and up‐regulation of phospho‐p‐38 MAPK, which was prevented by all drugs (p < .05). The number of microglial processes endpoints and the total branch length were lower in the untreated animals, but the overall immunolabeling of Iba‐1 was altered only in neuropathic rats (p < .05). The mean area of SGCs per neuron was significantly altered only in the inflammatory model (p < .05). All morphological alterations were reverted by modulating the fractalkine pathway (p < .05). In conclusion, the blockage of the fractalkine pathway seemed to be a possible therapeutic strategy for inflammatory and neuropathic orofacial pain, reducing mechanical hyperalgesia by impairing the phosphorylation of p‐38 MAPK and reverting morphological alterations in microglia and SGCs.

2023-12-21·Journal of Biomolecular Structure and Dynamics

A cystatin C similar protein from Musa acuminata that inhibits cathepsin B involved in rheumatoid arthritis using in silico approach and in vitro cathepsin B inhibition by protein extract

Article

作者: Chakraborty, Rajkumar ; Aggarwal, Kamal Krishan ; Rangra, Sabita ; Hasija, Yasha

Rheumatoid arthritis (RA) is an auto-immune disease that affects the synovial lining of the joints, causes synovitis and culminates to joint destruction. Cathepsin B is responsible for digesting unwanted proteins in extracellular matrix but its hyper expression could implicate in pathological diseases like RA. Available treatments for RA are classified into non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and steroids, but the severe side effects associated with these drugs is one of concerns and cannot be ignored. Thus, any alternative therapy with minimum or no side effects would be a cornerstone. In our in silico studies a cystatin C similar protein (CCSP) has been identified from Musa acuminata that could effectively inhibit the cathepsin B activity. In silico and molecular dynamics studies showed that the identified CCSP and cathepsin B complex has binding energy -66.89 kcal/mol as compared to cystatin C - cathepsin B complex with binding energy of -23.38 kcal/mol. These results indicate that CCSP from Musa acuminata has better affinity towards cathepsin B as compared to its natural inhibitor cystatin C. Hence, CCSP may be suggested as an alternative therapeutic in combating RA by inhibiting its one of the key proteases cathepsin B. Further, in vitro experiments with fractionated protein extracts from Musa sp. peel inhibited cathepsin B to 98.30% at 300 µg protein concentration and its IC₅₀ was found to be 45.92 µg indicating the presence of cathepsin B inhibitor(s) in protein extract of peel which was further confirmed by reverse zymography.Communicated by Ramaswamy H. Sarma.

项与 BF/PC-18 相关的新闻（医药）

2024-03-11

·BioSpace

ORIC Pharmaceuticals Reports Fourth Quarter and Full Year 2023 Financial Results and Operational Updates

Presented initial Phase 1b data from three clinical programs that support potential best in class pro with ORIC-944 and ORIC-114 prioritized for further advancement towards registrational studies Initiation of combination study of ORIC-944 with AR inhibitor(s) in metastatic prostate cancer expected in first half of 2024 and program update expected in mid-2024 Initiation of multiple dose expansion cohorts for ORIC-114 in patients with mutated NSCLC expected in first half of 2024 and updated Phase 1b data expected in first half of 2025 Strengthened cash position with $210 million from two private placement financings; cash and investments expected to fund operating plan into late 2026 SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, March 11, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc., (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today reported financial results and operational updates for the quarter and year ended December 31, 2023. “We’ve made significant progress over the past year as we presented initial positive data readouts across our three clinical programs, ORIC-114, ORIC-944 and ORIC-533, demonstrating their potential as best-in-class cancer therapeutics,” said Jacob M. Chacko, M.D., president and chief executive officer. “We strengthened our balance sheet with the completion of two PIPE financings totaling $210 million from top-tier healthcare specialist funds and prioritized our clinical pipeline around ORIC-114 and ORIC-944. We are building on the momentum generated in 2023 with multiple clinical milestones planned through the first half of 2025 as we advance two programs towards the initiation of registrational studies in the second half of 2025.” Fourth Quarter 2023 and Other Recent Highlights ORIC-114:a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor Presented initial data from the Phase 1b dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the ESMO Congress 2023. Initial data demonstrated potential best-in-class pro heavily pretreated patients, with 81% of patients having received prior EGFR exon 20 targeted agents and 86% having CNS metastases at baseline. Data from 50 patients showed favorable safety and both systemic and CNS responses, including the first reported systemic and CNS confirmed complete response in a patient with active brain metastases. Presented preclinical data for ORIC-114 at ESMO Congress 2023, demonstrating potent activity across atypical mutations in EGFR, thus expanding the potential eligible patient population. Expect to initiate dose expansion of Phase 1b trial in multiple cohorts in the first half of 2024 and expect to report updated Phase 1b data in the first half of 2025. ORIC-944:a potent and selective allosteric inhibitor of PRC2 In January 2024, reported initial Phase 1b monotherapy data in metastatic prostate cancer demonstrating the potential of ORIC-944 as a best-in-class therapeutic, including half-life greater than 10 hours, robust target engagement and well tolerated safety profile, supporting advancement for combination development. Expect to initiate combination study with AR inhibitor(s) in the first half of 2024 and provide a program update in mid-2024. ORIC-533: a highly potent, orally bioavailable small molecule inhibitor of CD73 Presented initial data from the Phase 1b trial of ORIC-533 in patients with relapsed/refractory multiple myeloma at the 2023 ASH Annual Meeting. Initial data demonstrated preliminary evidence of clinical antimyeloma activity and predicted immune effects from preclinical models, as well as a clean safety profile, with only grade 1 and 2 treatment-related events in heavily pre-treated patients. Expect to complete dose escalation for the Phase 1b trial of ORIC-533 in the first quarter of 2024, and the company plans to pursue strategic partnership for combination studies. Discovery Pipeline: Presented preclinical data confirming the therapeutic potential of highly selective PLK4 inhibitors as a synthetic lethal therapy for TRIM37 amplified breast cancers at the 2023 AACR Annual Meeting. Advanced ORIC-613, a novel, highly selective PLK4 inhibitor, through IND enabling studies. Corporate Highlights: Strengthened cash position with $85 million and $125 million private placement financings from new and existing healthcare specialist funds in June 2023 and January 2024, respectively. Fourth Quarter and Full Year 2023 Financial Results Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments totaled $235.0 million as of December 31, 2023. Including the $125.0 million private placement in January 2024, as of January 31, 2024 the Company had $351.8 million (unaudited) in cash, cash equivalents and investments, which is expected to fund the current operating plan into late 2026. R&D Expenses: Research and development (R&D) expenses were $24.5 million for the three months ended December 31, 2023, compared to $16.3 million for the three months ended December 31, 2022, an increase of $8.2 million. For the year ended December 31, 2023, R&D expenses were $85.2 million compared to $61.7 million for the same period of 2022, an increase of $23.5 million. The increases were due to a net increase in external expenses related to the advancement of product candidates and discovery programs, as well as higher personnel costs. G&A Expenses: General and administrative (G&A) expenses were $6.9 million for the three months ended December 31, 2023, compared to $5.8 million for the three months ended December 31, 2022, an increase of $1.1 million. The increase was primarily due to higher professional fees and personnel costs. For the year ended December 31, 2023, G&A expenses were $25.6 million compared to $25.1 million for the same period of 2022, an increase of $0.5 million. The increase was primarily due to higher personnel costs. IPR&D Expenses: Acquired in-process research and development (IPR&D) expenses of $5.0 million for the year ended December 31, 2022, were due to a development milestone payment related to ORIC-114. There were no such expenses for the year ended December 31, 2023. About ORIC Pharmaceuticals, Inc. ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by Overcoming Resistance In Cancer. ORIC’s clinical stage product candidates include (1) ORIC-114, a brain penetrant inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, being developed across multiple genetically defined cancers, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) ORIC-533, an orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy- and immunotherapy-based treatment regimens, being developed for multiple myeloma. Beyond these three product candidates, ORIC is also developing multiple precision medicines targeting other hallmark cancer resistance mechanisms. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to , and follow us on X or LinkedIn. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the continued clinical development of ORIC-114 and ORIC-944; ORIC-114, ORIC-944 and ORIC-533 clinical outcomes, which may materially change as patient enrollment continues or more patient data become available; the development plans and timelines for ORIC-114, ORIC-944 and ORIC’s other product candidates; the potential advantages of ORIC-114 and ORIC-944 and ORIC’s other product candidates and programs; plans underlying ORIC’s clinical trials and development; anticipated program milestones, including timing of the initiation of studies and program and data updates; the period over which ORIC estimates its existing cash, cash equivalents and investments will be sufficient to fund its current operating plan; and statements by the company’s chief executive officer. Words such as “believes,” “anticipates,” “plans,” “expects,” “intends,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. The forward-looking statements contained herein are based upon ORIC’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those projected in any forward-looking statements due to numerous risks and uncertainties, including but not limited to: risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early clinical stage company; ORIC’s ability to develop, initiate or complete preclinical studies and clinical trials for, obtain approvals for and commercialize any of its product candidates; changes in ORIC’s plans to develop and commercialize its product candidates; the potential for clinical trials of ORIC’s product candidates to differ from preclinical, initial, interim, preliminary or expected results; negative impacts of health emergencies, economic instability or international conflicts on ORIC’s operations, including clinical trials; the risk of the occurrence of any event, change or other circumstance that could give rise to the termination of ORIC’s license and collaboration agreements; the potential market for ORIC’s product candidates, and the progress and success of competing therapeutics currently available or in development; ORIC’s ability to raise any additional funding it will need to continue to pursue its business and product development plans; regulatory developments in the United States and foreign countries; ORIC’s reliance on third parties, including contract manufacturers and contract research organizations; ORIC’s ability to obtain and maintain intellectual property protection for its product candidates; the loss of key scientific or management personnel; competition in the industry in which ORIC operates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in ORIC’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (the “SEC”) on March 11, 2024, and ORIC’s future reports to be filed with the SEC. These forward-looking statements are made as of the date of this press release, and ORIC assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Contact: Dominic Piscitelli, Chief Financial Officer dominic.piscitelli@oricpharma.com info@oricpharma.com ORIC PHARMACEUTICALS, INC. CONDENSED BALANCE SHEETS (in thousands, except share and per share amounts) December 31, 2023 2022 Assets Current assets: Cash, cash equivalents and short-term investments $ 208,187 $ 206,272 Prepaid expenses and other current assets 4,410 4,185 Total current assets 212,597 210,457 Long-term investments 26,852 21,951 Property and equipment, net 2,862 3,253 Other assets 9,696 11,517 Total assets $ 252,007 $ 247,178 Liabilities and Stockholders' Equity Current liabilities: Accounts payable $ 944 $ 1,320 Accrued liabilities 19,514 14,068 Total current liabilities 20,458 15,388 Other long-term liabilities 7,461 9,439 Total liabilities 27,919 24,827 Total stockholders' equity 224,088 222,351 Total liabilities and stockholders' equity $ 252,007 $ 247,178 ORIC PHARMACEUTICALS, INC. STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (Unaudited) (in thousands, except share and per share amounts) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 Operating expenses: Research and development $ 24,481 $ 16,295 $ 85,172 $ 61,680 General and administrative 6,947 5,824 25,608 25,087 Acquired in-process research and development — — — 5,000 Total operating expenses 31,428 22,119 110,780 91,767 Loss from operations (31,428 ) (22,119 ) (110,780 ) (91,767 ) Other income, net 3,098 1,272 10,083 2,645 Net loss $ (28,330 ) $ (20,847 ) $ (100,697 ) $ (89,122 ) Other comprehensive income (loss): Unrealized gain (loss) on investments 627 456 1,549 (1,188 ) Comprehensive loss $ (27,703 ) $ (20,391 ) $ (99,148 ) $ (90,310 ) Net loss per share, basic and diluted $ (0.49 ) $ (0.52 ) $ (1.96 ) $ (2.25 ) Weighted-average shares outstanding, basic and diluted 57,464,041 40,125,286 51,450,848 39,655,260

临床1期财报临床结果AACR会议

2023-02-02

·Endpoints

Tonix snaps up assets from Healion Bio; Mesoblast gives its BLA another shot

New Jersey-based Tonix Pharmaceuticals is adding several assets to its portfolio in its latest move. The biotech announced Thursday it has acquired all assets belonging to Healion Bio. However, financial details were not disclosed. Healion’s assets include some small-molecule antiviral candidates. Tonix has labeled one of its pickups as TNX-3900, previously known as HB-121, a cathepsin protease inhibitor meant to work against SARS-CoV-2. While the antiviral candidate is currently being tested to counter to SARS-CoV-2, Tonix said in its release that it believes that it has other antiviral capabilities. However, the details of what TNX-3900 will be going after were not immediately available. “We are excited to develop Healion’s drug programs that include TNX-3900, which is a class of drugs with potential broad-spectrum anti-viral activity, either as monotherapies or in combination with other antivirals. Broad-spectrum antiviral agents have the potential to reduce viral load and allow the adaptive immune system to alert the other arms of the immune system to mount a protective response,” said Seth Lederman, Tonix’s CEO in a release . Tonix certainly needs a lift, as the biotech spent a good portion of 2022 hovering above or within the penny stock zone. The news today has driven its stock price $TNXP up 4%. In 2020, the FDA handed the Australian biotech Mesoblast a CRL for remestemcel-L, a treatment meant for children with steroid-refractory acute graft-versus-host disease (SR-aGVHD), with the FDA finding issue with the trial design. But now Mesoblast is heading back to the FDA. Mesoblast said in its announcement that the resubmission has new information that the FDA required in the 2020 CRL. In October of last year, Mesoblast stated that it was going forward on resubmission and eventually got a Fast Track designation for the candidate. The new resubmission will have a review period of up to six months. The resubmission includes new long-term survival data of the pediatric patients and information showing the treatment’s effect through four years. Mesoblast also included new data on remestemcel-L’s benefit in high-risk patients and a new analysis of the potency, among other pieces of data. “There is an urgent need for a therapy that improves the dismal survival outcome in children with SR-aGVHD. Our team has worked tirelessly over the past two years to provide a comprehensive response to the FDA. We are grateful for the agency’s active dialogue and constructive feedback that will ensure a high bar is met in terms of product consistency and predictability of clinical outcomes,” Mesoblast CEO Silviu Itescu said in a release .

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