Author: Benekareddy, Madhurima ; Maneshi, Mohammad Mehdi ; Thakur, Ashish ; Nelson, Brandon M. ; Nocek, Boguslaw ; Randolph, John T. ; Krishnan, Navasona ; Zoi, Ioanna ; Gopalakrishnan, Sujatha M. ; Dart, Michael J. ; Hutchins, Charles W. ; Shotwell, J. Brad ; Afanador, Gustavo A. ; Talaga, Lukas ; Sheehan, Mike M. ; Sunose, Mihiro ; Sadowski, Renee N. ; Karunan Partha, Sarathy ; Chapman, Alex M. ; Nacham, Omprakash ; Iu, Leo ; Panchal, Sanjay C. ; Shiroodi, Reza ; Brown, Jordan W. ; Bradley, Noah P. ; Smyth, Don ; Baikstis, Tomas ; Izquierdo-Ferrer, Javier ; O’Flynn, Daniel E. ; Bigelow, Lance ; Swensen, Andrew M. ; Jejurkar, Purvi C. ; Jain, Rinku ; Yarilina, Anna ; Montavon, Timothy J. ; Kurschner, Victoria A. ; Balakrishnan, Anand ; Hu, Dongjian

Abstract:

Herein, we report the discovery and optimization of a series of cluster of differentiation 38 (CD38) inhibitors derived from a virtual ligand screening (VLS) campaign. VLS identified imidazopyridazine hit 9, which was optimized to a novel and potent CD38 inhibitor peripheral tool 25 (A-8531) with an excellent pharmacokinetic profile. A cocrystal structure in addition to biophysical and biochemical characterization of 25 is consistent with uncompetitive inhibition of CD38 via the formation of covalent adduct 28. Further structure- and property-based modifications of 25 afforded sulfuryl pyrazole 39 (A-3190) with improved CNS distribution properties. Brain-penetrant thienopyrimidine 39 shows robust rodent pharmacokinetics and in vivo target engagement across skin, lung, liver, and brain, making it an excellent CD38 tool for the study of indications requiring engagement of CD38 in the brain.

01 Jul 2025·Translational Oncology

CD38 contributes to tumor progression and tumor microenvironment reshaping in epithelial ovarian cancer

Article

Author: Shan, Liyun ; Liu, Xiangnan ; Li, Yanli ; Li, Yingying ; Wang, Wei ; Xu, Shengjie ; Dai, Enci ; Liu, Yinping

BACKGROUND:

Ovarian cancer, ranking fifth in cancer mortality, presents a significant therapeutic challenge. The immunomodulatory functions of CD38in epithelial ovarian cancer (EOC) and its influence on the tumor microenvironment (TME) remain poorly understood.

METHODS:

Public datasets, RT-qPCR and immunohistochemistry (IHC) were used to analyze CD38 expression and clinicopathological features in EOC. Gene manipulation techniques were employed to elucidate its functions, while integrated IHC and bioinformatics were conducted to assess its involvement in immune/stromal infiltration. Immune-related functions of CD38 were explored using GO, KEGG analysis and TIP database. TIDE algorithm was employed to predict the correlation between CD38 and immune checkpoint blocking responsiveness. CD38 inhibitor efficacy was evaluated in an EOC mouse model, with flow cytometry monitoring cellular changes. The involvement of CD38 in the PI3K-AKT and IL-6 signaling pathways was evaluated using RT-qPCR, western blot, and publicly datasets.

RESULTS:

CD38 is significantly upregulated in EOC, influencing the cell proliferation and metastasis. It regulates the PI3K-AKT and IL-6 signaling pathways, thereby increasing tumor malignancy. CD38 is also upregulated in immune and stromal cells, affecting TME remodeling by facilitating immune cell and CAF infiltration, impeding T cell recognition of tumor cells, and enhancing CAF-tumor cell communication. Additionally, CD38 correlates with multiple immune checkpoint molecules. Notably, CD38 inhibitor therapy inhibited effectively EOC progression and modulates immune responses.

CONCLUSION:

Elevated CD38 expression is associated with EOC progression, TME remodeling, and immune response modulation. Thus, CD38 could be a promising target for ovarian cancer immunotherapy.

01 May 2024·EBioMedicine

Intratumoral CD38+CD19+B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinoma

Article

Author: Liu, Jiang ; Yu, Xianjun ; Wang, Wei ; Meng, Qingcai ; Hua, Jie ; Shi, Si ; Zhang, Bo ; Liang, Chen ; Zhu, Heng ; Xu, Jin

BACKGROUND:

The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies.

METHODS:

We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38⁺ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38⁺ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38⁺ B cells on antitumor immunity.

FINDINGS:

The presence of CD38⁺ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p < 0.001). Increased infiltration of CD38⁺ B cells was accompanied by reduced natural killer (NK) cells (p = 0.021) and increased regulatory T cells (p = 0.016). Molecular profiling revealed high expression of IL-10, IL-35, TGF-β, GZMB, TIM-1, CD5 and CD21, confirming their putative regulatory B cell-like features. Co-culture experiments demonstrated suppression of NK cell cytotoxicity by CD38⁺ B cell-derived IL-10 (p < 0.001). Finally, in vivo experiments suggested adoptive transfer of CD38⁺ B cells reduced antitumor immunity and administration of a CD38 inhibitor hampered tumor growth (p < 0.001).

INTERPRETATION:

We discovered regulatory B cell-like CD38⁺ B cell infiltration as an independent prognostic factor in PDAC. The use of CD38 inhibitor may provide new possibilities for PDAC immunotherapy.

FUNDING:

This study was supported by the National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Special Project for Clinical Research in the Health Industry of the Shanghai Health Commission (No. 20204Y0265) and Natural Science Foundation of Shanghai (23ZR1479300).

News (Medical) associated with CD38 Inhibitor(Ribon Therapeutics)

31 Dec 2025

·juvlabs.com

Eric Verdin, our collaborator in the Buck institute presents data on our compound

We were pleased to attend the Longevity Summit 2025 at the Buck Institute for Research on Aging, a vibrant gathering of leaders across aging science, biotechnology, and translational research, united by a shared commitment to advancing healthy aging. We were delighted to see Dr. Eric Verdin, President & CEO of the Buck Institute, present compelling new data on the role of CD38 in the aging brain and its contribution to cognitive decline. The presentation also highlighted data generated using NTX-748, Juvenescence®’s proprietary, highly selective and potent small-molecule CD38 inhibitor. This work reflects the strength of the ongoing collaboration between the Verdin Lab at the Buck Institute and Juvenescence, demonstrating how impactful partnerships can accelerate scientific discovery and therapeutic innovation. A meaningful highlight for both CD38 biology and the longevity field. Rosalba Perrone , Ph.D hashtag#LongevitySummit hashtag#BuckInstitute hashtag#AgingResearch hashtag#HealthyAging hashtag#Longevity hashtag#CD38 hashtag#NAD hashtag#Neuroscience hashtag#Biotech hashtag#Juvenescence hashtag#NapaTherapeutics hashtag#Research hashtag#Collaboration hashtag#TeamScience

31 Jul 2025

·juvlabs.com

Rosalba presenting data from our core medicine

🧬 This week our Senior Research Scientist Rosalba Perrone , Ph.D presented exciting new data from our CD38 inhibitor program at the 2025 Gordon Research Conferences on the Biology of Aging, alongside co-authors from our collaborators at the Buck Institute for Research on Aging. They shared new data highlighting how CD38 inhibition may enhance cognitive performance during aging by modulating NAD metabolism – reinforcing its potential as a key target in age related diseases. Our ongoing collaboration with the Buck Institute is helping us explore the broader therapeutic potential of this target across multiple indications beyond our current focus, including in brain function. 👏 Huge thanks to our scientific team and collaborators at the Buck for their groundbreaking work and shared commitment to advancing aging science. hashtag#AgingResearch hashtag#CD38 hashtag#NADMetabolism hashtag#BrainAging hashtag#DrugDiscovery hashtag#TranslationalScience hashtag#BiologyOfAging hashtag#Juvenescence hashtag#LongevityScience

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