AU-15330 / Dr. Reddy’s - LARVOL DELTA

Decipher androgen receptor condensate-mediated chromatin remodeling in gastric cancer (AACR 2025) - "The combination of enzalutamide and AU-15330 effectively suppressed cell proliferation, colony formation, and organoid viability. These findings suggest that AR's LLPS capacity plays a critical role in regulating its transcriptional activity. Furthermore, combining SWI/SNF inhibitors with AR antagonists showed synergistic effects in inhibiting GC cell proliferation."

Gastric Cancer • Oncology • Solid Tumor • AR • BRD4 • MBD4 • MED1

HBx-mediated Epigenetic Reprogramming through the ncBAF Complex to Promote HBV cccDNA Transcription (APASL 2025) - "AU15330, a PROTAC of BRG1/BRM, can significantly inhibit the replication of HBV and markedly reduce the accessibility of HBV cccDNA... This study suggested that HBx specifically recruits the ncBAF complex and overcomes heterochromatin barriers by regulating the interaction between BRD9 and histone acetylation, achieving epigenetic reprogramming of cccDNA to promote its transcription. This research could provide new targets and strategies for the prevention and treatment of hepatitis B, and it holds significant importance for controlling the progression of chronic hepatitis B disease. Table and Figure:Figure 1.HBx-mediated Epigenetic Reprogramming through the ncBAF Complex to Promote HBV cccDNA Transcription"

Hepatitis B • Hepatology • Inflammation • Targeted Protein Degradation • SMARCA4 • YY1

The SOX11 Interactome Reveals the SOX11:SMARCA4 Complex As a Driver of Oncogenic Transcriptional Programs in Mantle Cell Lymphoma (ASH 2024) - "AU-15330 treatment also reduced the expression of genes of other oncogenic pathways, such as the alternative NF-kB pathway and the anti-apoptotic BCL2-signaling of both Ibrutinib-resistant and -sensitive SOX11-positive cell lines, but not in JVM2. SMARCA4 upregulation, directly regulated by SOX11, is associated with poor MCL patient outcomes, highlighting its role in MCL pathogenesis. SOX11 : SMARCA4 complex commonly regulates the expression of critical genes for MCL, and the disruption of this complex could represent an innovative therapeutic strategy to overcome resistance and relapse to current therapies in MCL patients."

IO biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Targeted Protein Degradation • BCL2 • SMARCA4 • SOX11 • TP53

Degrading SMARCA2/4 Relieves the Differentiation Block in AML Via Chromatin Alterations Affecting S100A8/9 (ASH 2024) - "A novel and highly selective SMARCA2/4 and PBRM1 PROTAC degrading agent AU-15330 (Xiao et al., Nature 2022) was used to investigate the therapeutic effectiveness of targeting these BAF components in leukemic pathogenesis...Conclusions : Taken together, these studies elucidate a novel role of SMARCA2/4, as part of the BAF complex, in promoting leukemogenesis via regulation of alarmins (S100A8/9). Our data also demonstrates the in vivo and in vitro efficacy of degrading SMARCA2/4 in relieving the differentiation block seen in MDS/AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CD33 • CD34 • DNMT3A • FLT3 • NPM1 • PBRM1 • RUNX1 • S100A8 • S100A9 • SMARCA2 • TLR4 • TP53

ETS1 Recruits the Canonical Baf Complex to Reactivate the Hematopoietic Stem Cell MYB Enhancer in the T-Cell Leukemia Context (ASH 2024) - "Lastly, AU-15330, a PROTAC degrader of cBAF, impaired E-Me H3K27ac signals 2.1-11.1-fold and reduced MYB protein levels 2.3–9.7-fold...Finally, the literature provides ample examples of Notch having a central role in T-ALL. In contrast, we identify a top-ranked oncogenic enhancer that is independent of Notch but requires ETS1 to remodel chromatin to enable transcription factor complex assembly and function."

Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • ETS1 • LMO2 • MYB

Chromatin Helicase CHD6 Establishes Pro-inflammatory Enhancers and is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma. (PubMed, Cancer Res) - "The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities."

Journal • Synthetic lethality • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • CHD6 • FH • KEAP1 • SMARCA2

Investigating the distinct phase separation properties of androgen receptor isoforms in prostate cancer (PCF 2024) - "To assess the role of chromatin accessibility, we used PROTAC AU15330 to degrade the ATPases SMARCA2/4 of the SWI/SNF complex and evaluate their role in AR-V7 condensate formation. We also evaluated the interdependency between AR-FL and AR-V7 condensates by using ARV-110, a degrader of AR-FL, in PCa models...Conclusions AR-V7 forms phase-separated condensates that are crucial for transcriptional regulation in PCa, distinguishing its role from that of AR-FL. By identifying AR-V7 condensate-dependent programs, we can gain insights into androgen-independent pathways that may be explored for future drug targeting, offering potential new therapeutic strategies for managing aggressive PCa subtypes."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • KRAS • MBD4 • MED1 • SMARCA2

PROTACs targeting androgen receptor signaling: potential therapeutic agents for castration-resistant prostate cancer. (PubMed, Pharmacol Res) - "This technique has the potential to become the next generation of antitumor therapeutics as it could overcome the shortcomings of conventional small molecule inhibitors. In this review, we summarize the molecular mechanisms on PROTACs targeting AR signaling for CRPC, hoping to provide insights into drug development and clinical medication."

Journal • Review • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Sexual Disorders • Solid Tumor • Targeted Protein Degradation

SMARCA2/4 degraders relieve the differentiation block in AML via changes in chromatin looping and accessibility (AACR 2024) - "A novel and highly selective SMARCA2/4 and PBRM1 PROTAC degrading agent AU-15330 was used to investigate the therapeutic effectiveness of targeting BAF complexes as well as the role of SMARCA2/4 in leukemic pathogenesis...pBAF in the degrader treated cells improved engagement with target chromatin however, a decrease in the stability of the complex binding to the nucleosome when compared to DMSO treated cells was shown. Taken together, these studies will determine the role of SMARCA2/4 in leukemia disease."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • CD38 • PBRM1 • SMARCA2 • SMARCA4

Design, synthesis and activity of novel selective SMARCA2 degraders (ACS-Fall 2023) - "Recently, Aurigene Company identified SMARCA2/4 degrader AU-15330 using SMRACA2/4 BD domain inhibitor GEN-1 as a target protein recognition ligand...When tested in NCI-H568 cells at 1µM, the degradation rates of SMARCA2 by the two compounds were 88.1% and 83.9% respectively. Further structural edition and efficacy verification are underway."

Oncology • Targeted Protein Degradation • GEN1 • SMARCA2 • SMARCA4

Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas. (PubMed, Proc Natl Acad Sci U S A) - "The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells...Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • FOXO1 • PBRM1 • SMARCA2 • SMARCA4

Overcoming acquired resistance to PROTAC degraders (AACR 2023) - "Our study found that the mechanisms of resistance of PROTAC degraders can vary and may be dependent on drug concentrations. Such concepts may inform future clinical decision-making regarding drug dosing."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ABCB1 • ABCC1 • PBRM1 • SMARCA4