Abstract 6584: Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in cancer

作者: Medina, Julio ; Rivera-Molina, Yisel ; Schreiber, Taylor H. ; Mwangi, Joseph ; Morra, Marc ; Li, Kevin ; Bhatt, Ulhas ; Fromm, George ; Nguyen, Thuy-Ai Tran ; Oien, Nathan

AbstractWhile checkpoint inhibitor treatment has extended the survival of many cancer patients, most initial responders will later develop disease progression through a variety of poorly understood acquired resistance mechanisms (CPI-AR). One such recently described mechanism involves the transcriptional hyperactivation of genes associated with interferon (IFN) signaling, JAK/STAT, and antigen processing/presentation pathways. Aberrant IFN regulation in the setting of AR suggests that tumor cell intrinsic mechanisms have conferred a growth advantage despite the presence of immune-mediated pressure unleashed by PD-1/L1 antibody blockade. Analysis of transcripts progressively upregulated during acquisition of AR in vivo and transcripts upregulated by IFN exposure of isolated AR cell lines in vitro identified the E3 ubiquitin ligase TRIM7 as a candidate mediator of the AR phenotype. A specific pocket on the PRY/SPRY domain of TRIM7 has been shown to bind viral peptides, resulting in ubiquitination and degradation as a mechanism to mitigate viral propagation. Here we describe the evaluation of small molecule inhibitors (SMI) designed to the TRIM7 PRY/SPRY viral-pocket domain, where binding specificity was confirmed using mass spec analysis. These SMI competitively inhibited TRIM7 mediated stabilization of RACO-1, resulting in decreased cancer cell proliferation which was associated with altered c-Jun/AP-1 transcription. TRIM7 SMI also disrupted STING and MAVS ubiquitination and restored IFN responsiveness and sensitivity to PD-1 inhibitor treatment. Finally, given the position of TRIM7 downstream of growth factor receptor and kras signaling, combination of TRIM7 inhibitors with kras, braf, and/or MEK inhibitors was shown to additively suppress proliferation of tumor cells with kras mutations. These results provide evidence that upregulation of TRIM7 mediates both a pro-proliferative and IFN resistant phenotype in the setting of CPI-AR, and that inhibition of TRIM7 with small molecule inhibitors may prevent or reverse AR to PD-1/L1 blockade.Citation Format: Thuy-Ai Tran Nguyen, Marc Morra, Kevin Li, Ulhas Bhatt, Joseph Mwangi, Yisel Rivera-Molina, Nathan Oien, Julio Medina, Taylor H. Schreiber, George Fromm. Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6584.

2023-08-15·Bioorganic & medicinal chemistry letters

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications.

Article

作者: Li, Yihong ; Holan, Martin ; Lee, John ; Sperandio, David ; Wang, Sheldon ; Seidl, Frederick J ; Youngblood, Beth ; Bhatt, Ulhas ; Medina, Julio C ; McGee, Lawrence R ; Wei, Zhi-Liang ; Schwartz, Neil ; Gehlert, Donald ; Nerurkar, Alok ; Ding, Pingyu ; Nguyen, Thomas ; Li, Kevin ; Sadlowski, Corinne ; Widjaja, Tien

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

2023-01-01·Frontiers in psychiatry

EPD1504: a novel μ-opioid receptor partial agonist attenuates obsessive-compulsive disorder (OCD)-like behaviors.

Article

作者: Medina, Julio C ; Gehlert, Donald R ; Schwartz, Neil ; Youngblood, Beth

Low doses of μ-opioid receptor (MOR) agonists rapidly ameliorate symptoms in treatment-resistant obsessive-compulsive disorder (OCD) patients (10-50% of OCD patients). However, the utility of MOR agonists is limited by their safety liabilities. We developed a novel MOR partial agonist (EPD1540) that has an improved respiratory safety profile when compared to buprenorphine. Buprenorphine is a MOR partial agonist primarily used in the treatment of opiate-use disorder, which in investigator-led trials, has been shown to rapidly ameliorate symptoms in treatment-resistant OCD patients. In this study, we show that doses of EPD1504 and buprenorphine that occupy small fractions of MORs in the CNS (approximately 20%) are as effective as fluoxetine at ameliorating OCD-like behaviors in two different rat models (an operant probabilistic reversal task and marble burying). Importantly, effective doses of EPD1504 did not impair either locomotor activity, or respiration under normoxic or hypercapnic conditions. Additionally, EPD1504 had effects comparable to buprenorphine in the conditioned place preference assay. These results indicate that EPD1504 may provide a safer alternative to buprenorphine for the treatment of OCD patients.

项与 R2M Pharma, Inc. 相关的新闻（医药）

2022-08-01

·PRNewswire

BridGene Biosciences names David Sperandio, Ph.D., as Head of Chemistry

SAN JOSE, Calif., Aug. 1, 2022 /PRNewswire/ -- BridGene Biosciences, Inc., a biotechnology company using a proprietary chemoproteomics technology to discover and develop small molecules for high value, traditionally undruggable targets, today announced that David Sperandio, Ph.D., a medicinal chemist with more than 20 years' experience, has joined the company as the Head of Chemistry. Dr. Sperandio, an inventor on 23 patents and author of 25 peer-reviewed publications, has extensive experience leading cross-functional teams from molecule discovery through IND filing. Dr. Sperandio will lead the BridGene chemistry team and supervise research into covalent chemistry, chemical proteomics and quantitative mass spectrometry as methods for identifying undruggable targets. Additionally, Dr. Sperandio will be responsible for advancing BridGene's internal pipeline of first-in-class drugs for hard-to-drug targets in oncology. BridGene co-founder and CEO Ping Cao, Ph.D., commented, "David's addition to our leadership team and the recent Series B financing deepen BridGene's capabilities for using IMTAC™ to discover new drugs for novel and traditionally undruggable targets. David's leadership and experience will help expand BridGene's library of molecules to identify as potential drug candidates as we aim to advance a pipeline of first-in-class drugs for these new targets." Dr. Sperandio most recently served as an Executive Director at Biomea Fusion, where he led the team that identified BMF-500, a potential best-in-class targeted covalent FLT-3 inhibitor for the treatment of acute myeloid leukemia. Prior to joining Biomea Fusion, Sperandio led a collaboration of R2M Pharma Inc. with Tenaya Therapeutics Inc., which discovered novel HDAC6 inhibitors for cardiovascular diseases and was key for the clinical development of TN-301, an experimental treatment for heart failure. Dr. Sperandio started his career at Celera Corp. and focused on the structure-guided discovery of covalent reversible serine-protease inhibitors. He later moved to Gilead Sciences Inc., where he led the chemistry team that discovered Alobresib (GS-5829), a novel BRD4 inhibitor for prostate cancer, and Presatorvir (GS-5806), the first small molecule RSV fusion inhibitor that reached the clinic and showed proof of concept in men. Dr. Sperandio commented, "I am excited to join BridGene at such a dynamic time for the company. 2022 has been a remarkable year so far, and I look forward to working closely with the management team to continue to drive the success of IMTAC™." Dr. Sperandio obtained his doctoral degree in Organic Chemistry from the University of Zurich and completed his postdoctoral research at Stanford University. About BridGene Biosciences BridGene is a biotechnology company focused on discovering and developing innovative small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. By using its proprietary chemoproteomics platform, IMTAC™, BridGene can screen small molecules against proteins in live cells to discover drug candidates for high value and traditionally undruggable targets. For this purpose, BridGene takes advantage of its proprietary, diverse library of tagged, drug-like small molecules. The ultimate goal is to enable breakthrough small molecule drug discovery with expanded mechanisms to treat diseases with targets previously inaccessible to small molecules. The uniqueness of BridGene's technology allows it to perform IMTAC™ screening for both covalent and non-covalent molecules, target different amino acids and discover new targets for disease treatments by deconvoluting phenotypic screening hits. The company is advancing a diversified pipeline of first-in-class drugs for targets in multiple disease areas. For more information, visit . Contact Tiberend Strategic Advisors, Inc. Investors Jonathan Nugent +1-205-566-3026 [email protected] Media Bill Borden +1-732-910-1620 [email protected] Dave Schemelia +1-609-468-9325 [email protected] SOURCE BridGene Biosciences

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