| Structural highlights
Disease
SMCA2_HUMAN Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358. A rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time.[1] [2]
Function
SMCA2_HUMAN Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).[3]
Publication Abstract from PubMed
SMARCA2 and SMARCA4 are the core catalytic subunits of the SWI/SNF chromatin remodeling complex. Approximately 10% of non-small cell lung cancer (NSCLC) patients harbor SMARCA4 mutations, resulting in protein loss or loss-of-function (LOF) alterations. These SMARCA4-deficient cancers are highly dependent on SMARCA2 for proliferation, growth, and survival, making SMARCA2 a promising synthetic lethal target. Here, we developed and characterized PRT3789, a clinical-stage SMARCA2-selective targeted protein degrader (TPD). It induced polyubiquitination at lysine residues unique to SMARCA2 through stable ternary complex formation with the VHL E3 ligase. The selectivity was driven by interactions with an extended loop unique to SMARCA2, as revealed by structure-based analyses. PRT3789 promoted selective degradation of SMARCA2, while sparing its highly homologous paralog, SMARCA4. In SMARCA4-deficient models, SMARCA2 degradation disrupted SWI/SNF complex integrity by inducing dissociation of multiple subunits, leading to downstream transcriptional reprogramming. PRT3789 induced robust tumor growth inhibition and regression in SMARCA4-deficient models, both as monotherapy and in combination with targeted therapies or chemotherapies. In contrast, SMARCA4-wild-type models exhibited minimal response despite confirmed SMARCA2 degradation, consistent with SMARCA4 sparing and preserved SWI/SNF complex integrity. In clinical settings, PRT3789 reduced SMARCA2 protein levels in peripheral blood mononuclear cells (PBMCs) from patients with SMARCA4-mutated cancers. Initial signs of clinical activity have been observed, including RECIST-confirmed partial responses. Together, these findings demonstrate the selective targeting of SMARCA2 and the potential for a favorable therapeutic index with PRT3789. Phase I/II clinical trials with PRT3789 are ongoing in biomarker-selected patients with SMARCA4-mutated solid tumors.
PRT3789 is a First-in-Human SMARCA2-Selective Degrader that Induces Synthetic Lethality in SMARCA4-Mutated Cancers.,Hulse M, Wang M, Xu C, Carter J, Agarwal A, Lu L, Pitis P, Bhagwat N, Rager J, Kurian J, Basch C, Sivakumar M, Burtell J, Mondal A, Grego A, Moore A, Bachner C, Vykuntam K, Reichelderfer A, Park J, Cote J, Cowart M, Osinubi OP, Bigot L, Da Silva A, Nobre C, Meteau M, Soares M, Tang HY, Bersch K, Dai C, Cao G, Shen B, Emm T, Ruepp S, Xavier J, Tankersley C, Heiser D, Lee SH, Geeganage S, Ruggeri B, Lin H, Novotny W, Huang J, Vaddi K, Combs A, Scherle P, Ito K Cancer Res. 2025 Sep 24. doi: 10.1158/0008-5472.CAN-25-1141. PMID:40991405[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012 Mar 18;44(4):376-8. doi: 10.1038/ng.2219. PMID:22426308 doi:10.1038/ng.2219
- ↑ Van Houdt JK, Nowakowska BA, Sousa SB, van Schaik BD, Seuntjens E, Avonce N, Sifrim A, Abdul-Rahman OA, van den Boogaard MJ, Bottani A, Castori M, Cormier-Daire V, Deardorff MA, Filges I, Fryer A, Fryns JP, Gana S, Garavelli L, Gillessen-Kaesbach G, Hall BD, Horn D, Huylebroeck D, Klapecki J, Krajewska-Walasek M, Kuechler A, Lines MA, Maas S, Macdermot KD, McKee S, Magee A, de Man SA, Moreau Y, Morice-Picard F, Obersztyn E, Pilch J, Rosser E, Shannon N, Stolte-Dijkstra I, Van Dijck P, Vilain C, Vogels A, Wakeling E, Wieczorek D, Wilson L, Zuffardi O, van Kampen AH, Devriendt K, Hennekam R, Vermeesch JR. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat Genet. 2012 Feb 26;44(4):445-9, S1. doi: 10.1038/ng.1105. PMID:22366787 doi:10.1038/ng.1105
- ↑ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905-17. PMID:12837248
- ↑ Hulse M, Wang M, Xu C, Carter J, Agarwal A, Lu L, Pitis P, Bhagwat N, Rager J, Kurian J, Basch C, Sivakumar M, Burtell J, Mondal A, Grego A, Moore A, Bachner C, Vykuntam K, Reichelderfer A, Park J, Cote J, Cowart M, Osinubi OP, Bigot L, Da Silva A, Nobre C, Meteau M, Soares M, Tang HY, Bersch K, Dai C, Cao G, Shen B, Emm T, Ruepp S, Xavier J, Tankersley C, Heiser D, Lee SH, Geeganage S, Ruggeri B, Lin H, Novotny W, Huang J, Vaddi K, Combs A, Scherle P, Ito K. PRT3789 is a First-in-Human SMARCA2-Selective Degrader that Induces Synthetic Lethality in SMARCA4-Mutated Cancers. Cancer Res. 2025 Sep 24. PMID:40991405 doi:10.1158/0008-5472.CAN-25-1141
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