Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho β (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation ofKLBin these HCC cells resulted in a fitness defect more severe than that resulting from inactivation ofFGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed thatFGFR3restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.

2022-02-01·European Journal of Pharmacology3区 · 医学

The mechanism by which ATP regulates alcoholic steatohepatitis through P2X4 and CD39

3区 · 医学

Article

作者: Wu, Xue ; Fang, Qian ; Zhao, Ning ; Cai, Jun-Nan ; Xia, Guo-Qing ; Lv, Xiong-Wen

Alcoholic liver disease caused by chronic excessive drinking has become one of the most common types of liver disease. Alcohol-induced inflammatory immune responses play a central role in the development of alcohol-associated steatohepatitis. The content and expression of ATP and P2X4 in the livers of alcoholic steatohepatitis mice are significantly increased. The content of ATP increased by 20 percent and the expression of P2X4 receptor protein was 1.3 times higher than that in the livers of normal mice. Treatment with 5-BDBD, a P2X4 receptor-specific inhibitor, significantly reduced alcohol-induced liver inflammation and lipid deposition. In RAW264.7 cell experiments, 5-BDBD inhibited the expression of P2X4 and alleviated alcohol-induced inflammation, while the CD39-specific inhibitor POM-1 reduced extracellular ATP degradation and promoted the expression of P2X4, thereby exacerbating inflammation. After treatment with 5-BDBD, P2X4 receptor protein expression decreased by 0.2 times and after treatment with POM-1, P2X4 receptor protein expression increased by 0.1 times compared to the alcohol-stimulated group. In addition, inhibition of P2X4 expression in RAW264.7 cells reduced calcium influx in RAW264.7 cells. P2X4 may induce the activation of NLRP3 inflammasomes by mediating calcium influx, thus exacerbating the inflammatory response, and inhibition of P2X4 expression can effectively block this process. Conclusion: These results suggest that the ATP-P2X4 signaling pathway promotes the inflammatory response in alcoholic steatohepatitis and that CD39 may play a protective role in regulating P2X4 expression by hydrolyzing ATP. In conclusion, the CD39 and ATP-P2X4 signaling pathways may be potential therapeutic targets for alcoholic steatohepatitis.

2020-01-01·International Journal of Pharmaceutics

P-glycoprotein (ABCB1/MDR1) limits brain accumulation and Cytochrome P450-3A (CYP3A) restricts oral availability of the novel FGFR4 inhibitor fisogatinib (BLU-554)

Article

作者: El-Lari, Mujtaba ; Wang, Yaogeng ; Schinkel, Alfred H ; Beijnen, Jos H ; Lebre, Maria C ; Li, Wenlong ; Sparidans, Rolf

Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b^-/- (6.3-fold) and Abcb1a/1b;Abcg2^-/- mice (7.2-fold) compared to wild-type mice, but not in single Abcg2^-/- mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a^-^{^/}^- mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.

项与 FGFR4-specific inhibitor(Tyra Biosciences) 相关的新闻（医药）

2023-05-04

·PRNewswire

Tyra Biosciences Reports First Quarter 2023 Financial Results and Highlights

-SURF301 Phase 1/2 oncology study continues to advance- - Expanded TYRA-300 clinical development into achondroplasia- -IND for TYRA-200 cleared with Phase 1 study on track for 2H 2023- -Strong cash position of $241.7 million as of Q1 2023- CARLSBAD, Calif., May 4, 2023 /PRNewswire/ -- Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptor (FGFR) biology, today reported financial results for the quarter ended March 31, 2023 and highlighted recent corporate progress. "2023 is shaping up to be a great year for TYRA. We believe that our lead precision compound, TYRA-300, is well-positioned to become a best-in-class agent in multiple therapeutic areas where FGFR3 plays a major role. Our SURF301 oncology study is progressing well, and we look forward to providing more detail on our clinical plans for TYRA-300 in achondroplasia," said Todd Harris, CEO of TYRA. "In addition, we continued to advance our broader pipeline, with TYRA-200 expected to enter the clinic in 2H 2023, and additional clinical candidates from our in-house SNÅP discovery engine poised for nomination." First Quarter 2023 and Recent Corporate Highlights TYRA-300 Advanced SURF301 Phase 1/2 Study for Oncology. TYRA continued to advance its SURF301 Phase 1/2 clinical study of TYRA-300, an investigational agent and a once-daily oral FGFR3-selective inhibitor, with an initial focus on patients with metastatic urothelial carcinoma of the bladder and urinary tract. SURF301 ( Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors) (NCT05544552) is a multi-center, open label study designed to determine the optimal and maximum tolerated doses and the recommended Phase 2 dose of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. During the first quarter of 2023, TYRA continued to enroll and dose patients in SURF301 at multiple clinical sites. Expanded Development into Achondroplasia. In March 2023, TYRA announced the expansion of development of TYRA-300 into achondroplasia based on positive preclinical results in a study performed in collaboration with the Imagine Institute in Paris, France. TYRA is on track to submit an Investigational New Drug application (IND) to the U.S. Food and Drug Administration (FDA) to enable a Phase 2 study of TYRA-300 in pediatric achondroplasia in 2024. TYRA-200 IND Cleared by FDA; Phase 1 Study on Track for 2H 2023. In March 2023, TYRA announced that the FDA cleared its IND to proceed with a Phase 1 clinical study of TYRA-200, an FGFR1/2/3 inhibitor with potency against activating FGFR2 gene alterations and resistance mutations. The trial will be focused on intrahepatic cholangiocarcinoma resistant to prior FGFR inhibitors. TYRA expects the first patient will be dosed in this trial in the second half of 2023. SNÅP Platform and Pipeline TYRA continued to advance its in-house precision medicine discovery engine, SNÅP, to develop therapies in targeted oncology and genetically defined conditions including FGF19+/FGR4-driven cancers, and RET (REarranged during Transfection kinase) driven cancers. First Quarter 2023 Financial Results First quarter 2023 net loss was $11.9 million compared to $14.8 million for the same period in 2022. First quarter 2023 research and development expenses were $10.4 million compared to $9.6 million for the same period in 2022. First quarter 2023 general and administrative expenses were $3.9 million compared to $5.2 million for the same period in 2022. As of March 31, 2023, TYRA had cash and cash equivalents of $241.7 million that will support TYRA through important clinical and operational milestones over at least the next two years. About TYRA-300 TYRA-300 is the Company's lead precision medicine program stemming from its in-house SNÅP platform. TYRA-300 is an investigational, oral, FGFR3-selective inhibitor currently in development for the treatment of cancer and skeletal dysplasias including achondroplasia. TYRA-300 is being evaluated in a multi-center, open label Phase 1/2 clinical study, SURF301 ( Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors). SURF301 (NCT05544552) was designed to determine the optimal and maximum tolerated doses (MTD) and the recommended Phase 2 dose (RP2D) of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. SURF301 is currently enrolling adults with advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations. In skeletal dysplasias, TYRA-300 has demonstrated positive preclinical results and the Company expects to submit an IND for the initiation of a Phase 2 clinical study in pediatric achondroplasia in 2024. About Tyra Biosciences Tyra Biosciences, Inc. (Nasdaq: TYRA) is a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in FGFR biology. The Company's in-house precision medicine platform, SNÅP, enables rapid and precise drug design through iterative molecular SNÅPshots that help predict genetic alterations most likely to cause acquired resistance to existing therapies. TYRA's initial focus is on applying its accelerated small molecule drug discovery engine to develop therapies in targeted oncology and genetically defined conditions. TYRA is based in Carlsbad, CA. For more information about our science, pipeline and people, please visit and engage with us on LinkedIn. Forward-Looking Statements TYRA cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the potential to develop next-generation precision medicines, the potential safety and therapeutic benefits of TYRA-300 and other product candidates and the potential for TYRA-300 to become a best-in-class agent; the expectation to nominate clinical candidates from our FGF19+/FGFR4 and RET programs; the sufficiency of our cash position; expected cash runway; the expected timing and phase of clinical development of TYRA-300 and TYRA-200; and the potential for SNÅP to develop therapies in targeted oncology and genetically defined conditions. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: we are early in our development efforts, have only recently begun testing our lead product candidate in clinical trials and the approach we are taking to discover and develop drugs based on our SNÅP platform is novel and unproven and it may never lead to product candidates that are successful in clinical development or approved products of commercial value; potential delays in the commencement, enrollment, and completion of preclinical studies and clinical trials; results from preclinical studies or early clinical trials not necessarily being predictive of future results; our dependence on third parties in connection with manufacturing, research and preclinical testing; acceptance by the FDA of INDs or of similar regulatory submissions by comparable foreign regulatory authorities for the conduct of clinical trials of TYRA-300 in pediatric achondroplasia; an accelerated development or approval pathway may not be available for TYRA-300 or other product candidates and any such pathway may not lead to a faster development process; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization; the potential for our programs and prospects to be negatively impacted by developments relating to our competitors, including the results of studies or regulatory determinations relating to our competitors; our ability to maintain undisrupted business operations due to the COVID-19 pandemic or other epidemic diseases, including delaying or disrupting our preclinical studies and clinical trials, manufacturing, and supply chain; regulatory developments in the United States and foreign countries; we may use our capital resources sooner than we expect; unstable market and economic conditions and adverse developments with respect to financial institutions and associated liquidity risk may adversely affect our business and financial condition and the broader economy and biotechnology industry; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading "Risk Factors" in our annual report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contact: Amy Conrad [email protected] SOURCE Tyra Biosciences, Inc.

临床1期财报临床申请临床结果临床2期

2023-03-29

·PRNewswire

Tyra Biosciences to Participate in Upcoming Investor Conferences

CARLSBAD, Calif., March 29, 2023 /PRNewswire/ -- Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptor (FGFR) biology, today announced that management will present and participate in the following investor conferences: Cantor's The Future of Oncology Virtual Symposium Todd Harris, CEO of TYRA, will participate virtually in a fireside chat on Tuesday, April 4, 2023, at 2:15 pm ET Bank of America 2023 Healthcare Conference Mr. Harris will present on Thursday, May 11, 2023, at 9:35 am PT A live and archived webcast of the Bank of America event will be available via the For Investors page on the Investor section of the TYRA website. About Tyra Biosciences Tyra Biosciences, Inc. (Nasdaq: TYRA) is a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in FGFR biology. The Company's in-house precision medicine platform, SNÅP, enables rapid and precise drug design through iterative molecular SNÅPshots that help predict genetic alterations most likely to cause acquired resistance to existing therapies. TYRA's initial focus is on applying its accelerated small molecule drug discovery engine to develop therapies in targeted oncology and genetically defined conditions. TYRA is based in Carlsbad, CA. For more information about our science, pipeline and people, please visit and engage with us on LinkedIn. Contact: Amy Conrad [email protected] SOURCE Tyra Biosciences

2023-03-01

·PRNewswire

Tyra Biosciences Expands Development of TYRA-300, an Oral FGFR3 Selective Agent, into Achondroplasia

- In preclinical models, TYRA-300 demonstrated significant increases in growth and bone length- -Phase 2 clinical study for pediatric achondroplasia planned to be initiated in 2024- -Conference call and webcast today, March 1st, at 8:00 am ET- CARLSBAD, Calif., March 1, 2023 /PRNewswire/ -- Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptors (FGFR) biology, today announced that it is expanding development of TYRA-300 into achondroplasia (ACH) based on positive preclinical results demonstrated in a study performed in collaboration with the Imagine Institute in Paris, France. Achondroplasia, the most common form of dwarfism, is a skeletal dysplasia in which growth plate cartilage is affected, resulting in decreased growth of the long bones, vertebral bodies and skull base. These growth differences result in health complications such as cranial and spinal stenosis, hydrocephalus and sleep apnea. A specific mutation in FGFR3 causes over 97% of achondroplasia. TYRA-300, an investigational agent, is a once-daily oral FGFR3 selective inhibitor whose design may have a meaningful impact on achondroplasia and other skeletal dysplasias. In the study, TYRA-300 was evaluated in FGFR3 wild-type and mutant preclinical models to measure increases in growth and bone length, compared to vehicle-treated mice. In an FGFR3 Y367C/+ model, TYRA-300 was administered daily at a 1.2 mg/kg dose for 15 days. TYRA-300 increased body length in mice by 17.6% compared to the vehicle (p<0.0001) and increased the length of the femur (+24.4%), tibia (+38.3%) and L4-L6 (+23.9%) in mice (p<0.0001). "Our design goal for TYRA-300 was to develop a competitive FGFR3 inhibitor that overcomes the significant liabilities of approved agents, including tolerability, off-target toxicities, and acquired resistance," said Todd Harris, CEO of TYRA. "The encouraging results seen to date with TYRA-300 in key oncology and skeletal dysplasia models provide us great confidence to expand our pipeline beyond targeted oncology and pursue genetic conditions like achondroplasia." Dr. Laurence Legeai-Mallet, who led the research, added, "We are very excited about the initial results of TYRA-300 in our skeletal dysplasia mouse model, given our deep experience with multiple clinical agents in the FGFR3 related skeletal dysplasia space. The increases in animal growth and bone length with TYRA-300 are promising. We look forward to working with TYRA on further development." Dr. Legeai-Mallet is director of research at Institut National de la Santé et de la Recherche Médicale (INSERM), and head of the Laboratory "Molecular and Physiopathological Bases of Osteochondrodysplasia" at the Imagine Institute (Paris, France). "Children with achondroplasia often have medical complications that are not being addressed with current therapies - such as spinal stenosis, genu vara and sleep apnea - and I'm pleased that TYRA is pursuing clinical development," said Dr. Michael Bober, Medical Director of the Skeletal Dysplasia Program, Nemours Children's Hospital, Delaware. "TYRA-300 is an exciting new oral option targeting the FGFR3 pathway directly that I believe could have a life-changing impact for children with achondroplasia." Hiroomi Tada, M.D., Ph.D., CMO of TYRA, commented, "We are working on a development plan to deliver a potentially safe and convenient oral therapy to address the unmet needs of children with achondroplasia. We look forward to submitting an IND to enable a Phase 2 study in pediatric achondroplasia in 2024." In addition, TYRA continues to progress its pipeline and reports that the U.S. Food and Drug Administration (FDA) cleared its IND to proceed with a Phase 1 clinical study of TYRA-200, an FGFR1/2/3 inhibitor with potency against activating FGFR2 gene alterations and resistance mutations. This trial is expected to dose the first patient in the second half of 2023. Conference Call & Webcast Information TYRA will host a conference call and webcast today, March 1, 2023 at 8:00 a.m. ET. The conference call can be accessed by dialing 1-646-968-2525 for domestic callers and 1-888-596-4144 for international callers. Please provide the operator with the passcode 7533836 to join the conference call. The conference call will also be available via webcast under the "For Investors" section of TYRA's website at . An archive of the teleconference and webcast will also be made available on TYRA's website following the call. About TYRA-300 TYRA-300 is the Company's lead precision medicine program stemming from its in-house SNÅP platform. TYRA-300 is an investigational, oral, FGFR3-selective inhibitor currently in development for the treatment of cancer and skeletal dysplasias including achondroplasia. TYRA-300 is being evaluated in a multi-center, open label Phase 1/2 clinical study, SURF301 ( Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors). SURF301 (NCT05544552) was designed to determine the optimal and maximum tolerated doses (MTD) and the recommended Phase 2 dose (RP2D) of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. SURF301 is currently enrolling adults with advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations. In skeletal dysplasias, TYRA-300 has demonstrated positive preclinical results and the Company expects to submit an IND for the initiation of a Phase 2 clinical study in pediatric achondroplasia in 2024. About Tyra Biosciences Tyra Biosciences, Inc. (Nasdaq: TYRA) is a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in FGFR biology. The Company's in-house precision medicine platform, SNÅP, enables the rapid and precise refinement of structural drug design through iterative molecular SNÅPshots that help predict genetic alterations most likely to cause acquired resistance to existing therapies. TYRA's initial focus is on applying its accelerated small molecule drug discovery engine to develop therapies in targeted oncology and genetically defined conditions. TYRA is based in Carlsbad, CA. For more information about our science, pipeline and people, please visit and engage with us on LinkedIn. Forward-Looking Statements TYRA cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the potential to develop next-generation precision medicines and the potential safety and therapeutic benefits of TYRA-300; and the expected timing and phase of clinical development of TYRA-300 in pediatric achondroplasia and TYRA-200. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: we are early in our development efforts, have only recently begun testing our lead product candidate in clinical trials and the approach we are taking to discover and develop drugs based on our SNÅP platform is novel and unproven and it may never lead to product candidates that are successful in clinical development or approved products of commercial value; potential delays in the commencement, enrollment, and completion of preclinical studies and clinical trials; results from preclinical studies or early clinical trials not necessarily being predictive of future results; our dependence on third parties in connection with manufacturing, research and preclinical testing; acceptance by the FDA of INDs or of similar regulatory submissions by comparable foreign regulatory authorities for the conduct of clinical trials of TYRA-300 in pediatric achondroplasia; an accelerated development or approval pathway may not be available for TYRA-300 or other product candidates and any such pathway may not lead to a faster development process; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization; the potential for our programs and prospects to be negatively impacted by developments relating to our competitors, including the results of studies or regulatory determinations relating to our competitors; our ability to maintain undisrupted business operations due to the COVID-19 pandemic or other epidemic diseases, including delaying or disrupting our preclinical studies and clinical trials, manufacturing, and supply chain; regulatory developments in the United States and foreign countries; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading "Risk Factors" in our annual report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contact: Amy Conrad [email protected] SOURCE Tyra Biosciences

临床2期临床结果临床1期临床申请

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