PBRM1 inhibitors(Protein polybromo-1 inhibitors), SMARCA2 inhibitors(Probable global transcription activator SNF2L2 inhibitors), SMARCA4 inhibitors(Transcription activator BRG1 inhibitors)

+ [1]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid LeukemiaMyelodysplastic Syndromes

Inactive Indication

Prostatic Cancer

Originator Organization

University of Michigan

Active Organization

Aurigene Oncology Ltd.

Albert Einstein College of Medicine, Inc.

Inactive Organization

University of Michigan

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC39H49N9O5S

InChIKeyHDCCMCFIGHIDJR-TUDDPRDOSA-N

CAS Registry2380274-50-8

100 Clinical Results associated with AU-15330

100 Translational Medicine associated with AU-15330

100 Patents (Medical) associated with AU-15330

Literatures (Medical) associated with AU-15330

01 Aug 2024·Cancer Cell

Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

Article

Author: Mannan, Rahul ; Samajdar, Susanta ; Mahapatra, Somnath ; Hou, Siyu ; Su, Fengyun ; Rudin, Charles M ; Wu, Xiaoli S ; Young, Eleanor ; Wang, Xiaoju ; Miner, Stephanie J ; Redin, Esther ; Chinnaiyan, Arul M ; He, Tongchen ; Qiao, Yuanyuan ; Ramachandra, Murali ; Bao, Yi ; Ching-Yi Tien, Jean ; Zheng, Heng ; Klingbeil, Olaf ; Cho, Hanbyul ; Cao, Xuhong ; Eyunni, Sanjana ; Zheng, Yang ; Dhanasekaran, Saravana M ; Mehra, Rohit ; Talpaz, Moshe ; Kim, NamHoon ; Parolia, Abhijit ; Xiao, Lanbo ; Kandarpa, Malathi ; Abbineni, Chandrasekhar ; Vakoc, Christopher R

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

01 Aug 2024·Cancer Cell

Transcription factor dependencies identify BAF-dependent cancers

Article

Author: Hargreaves, Diana C ; McRae, Helen M

In Cancer Cell, Bolomsky et al., Duplaquet et al., and He et al. identify cancers that are dependent on the BAF chromatin remodeling complex, specifically IRF4-driven multiple myeloma and POU2F3-subtype small cell lung cancer, highlighting potential therapeutic applications for BAF complex inhibitors/degraders.

02 May 2023·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas.

Q1 · CROSS-FIELD

Article

Author: Chinnaiyan, Arul M ; Yang, Fusheng ; Mota, Mateus ; Sweha, Stefan R ; Judkins, Alexander R ; Pun, Matt ; Cao, Xuhong ; Xiao, Lanbo ; Samajdar, Susanta ; Venneti, Sriram ; Parolia, Abhijit ; Natarajan, Siva Kumar ; Chung, Chan ; Hawes, Debra ; Ding, Yujie

Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling switch/sucrose nonfermentable (SWI/SNF) complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2, and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. 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. AU-15330 lowered chromatin accessibility measured by ATAC-Seq at nonpromoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in the levels of FOXO1, a key member of the forkhead family of transcription factors. 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.

100 Deals associated with AU-15330

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Phase 2	United States	University of Michigan	22 Dec 2021
Acute Myeloid Leukemia	Preclinical	India	Aurigene Oncology Ltd.	08 Dec 2024
Acute Myeloid Leukemia	Preclinical	United States	Albert Einstein College of Medicine, Inc.	08 Dec 2024
Myelodysplastic Syndromes	Preclinical	India	Aurigene Oncology Ltd.	08 Dec 2024
Myelodysplastic Syndromes	Preclinical	United States	Albert Einstein College of Medicine, Inc.	08 Dec 2024

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