Watch the recording now: Illuminating the role of SMARCA2/4 in childhood alveolar rhabdomyosarcoma by targeted protein degradation with ACBI1
20 January 2023
Illuminating the role of SMARCA2/4 in a childhood rhabdomyosarcoma by targeted protein degradation with ACBI1
Watch the recording of our opnMe online seminar from Nov 29, 2022, and follow the journey of the PROTAC ACBI1, a cooperative degrader of BAF subunits SMARCA2 and 4, which are essential parts of the chromatin remodeler BAF (SWI/SNF) complex.
Speakers:
Alessio Ciulli, Center for Targeted Protein Degradation, University of Dundee, UK
Manfred Koegl, Cancer Research, Boehringer Ingelheim
Charles Keller, Children’s Cancer Therapy Development Institute, Beaverton, US
Beat Schäfer, University Children‘s Hospital Zurich, CH
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About SMARCA2/4 degrader ACBI1:
ACBI1 is a potent and cooperative PROTAC degrader of the BAF chromatin remodeling ATPase subunits SMARCA2 and SMARCA4, as well as the facultative BAF complex subunit PBRM. It harnesses the von-Hippel-Landau (VHL) E3 ligase to recruit its targets via their bromodomains. The molecule is the result of an elegant two-step structure-based drug design, whereby co-crystallization of the ternary complexes of precursor containing the SMARCA2 bromodomain and VHL yielded the optimized molecule. It was used to successfully exploit cancer vulnerabilities in vitro and in vivo, unveiling the biology behind SMARCA2 and SMARCA4.1
About opnMe:
opnMe.com, the new open innovation portal of Boehringer Ingelheim, aims to accelerate research initiatives to enable new insights of disease biology in areas of high unmet medical need by sharing well-characterized molecules and offer collaborations for science. In the spirit of collaboration, our molecules are provided to the scientific community to help unlock and fulfil their full potential. These molecules are either freely available as “Molecules to Order” or applied via scientific research submissions as “Molecules for Collaboration”. As part of our third pillar, our “opn2EXPERTS” program, we also enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs.
References:
1 Farnaby W., Koegl M., Roy M. J., Whitworth C., Diers E., Trainor N., Zollman D., Steurer S., Karolyi-Oezguer J., Riedmueller C., Gmaschitz T., Wachter J., Dank C., Galant M., Sharps B., Rumpel K., Traxler E., Gerstberger T., Schnitzer R., Petermann O., Greb P., Weinstabl H., Bader G., Zoephel A., Weiss-Puxbaum A., Ehrenhöfer-Wölfer K., Wöhrle S., Boehmelt G., Rinnenthal J., Arnhof H., Wiechens N., Wu M-Y., Owen-Hughes T., Ettmayer P., Pearson M., McConnell D. B., Ciulli A. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019, 15(7):672-680. DOI: 10.1038/s41589-019-0294-6, PubMed.
2 Bharathy N., Cleary M. M., Kim J-A., Nagamori K., Crawford K. A., Wang E., Saha D., Settelmeyer T. P., Purohit R., Skopelitis D., Chang K., Doran J. A., Kirschbaum C. W., Bharathy S., Crews D. W., Randolph M. E., Karnezis A. N., Hudson-Price L., Dhawan J., Michalek J. E., Ciulli A., Vakoc C. R., Keller C. SMARCA4 biology in alveolar rhabdomyosarcoma. Oncogene 2022, 41, 1647–1656. DOI: 10.1038/s41388-022-02205-0, PubMed.
3 Laubscher D., Gryder B. E., Sunkel B. D., Andresson T., Wachtel M., Das S., Roschitzki B., Wolski W., Wu X. S., Chou H-C., Song Y. K., Wang C., Wei J. S., Wang M., Wen X., Ai Ngo Q., Marques J. G., Vakoc C. R., Schäfer B. W., Stanton B. Z., Khan J. BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma. Nat Commun. 2021, 12(1):6924. DOI: 10.1038/s41467-021-27176-w, PubMed.