Repository Community: null
http://hdl.handle.net/20.500.11750/1162
2024-03-28T16:33:03Z
2024-03-28T16:33:03Z
Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
Lim, Ye Seul
Yoo, Sun-Mi
Patil, Vineet
Kim, Han Wool
Kim, Hyun-Hwi
Suh, Beomseon
Park, Ji Youn
Jeong, Na-rae
Park, Chi Hoon
Ryu, Je Ho
Lee, Byung-Hoon
Kim, Pilho
Lee, Song Hee
http://hdl.handle.net/20.500.11750/17242
2024-03-26T05:10:19Z
2022-12-31T15:00:00Z
Title: Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models
Author(s): Lim, Ye Seul; Yoo, Sun-Mi; Patil, Vineet; Kim, Han Wool; Kim, Hyun-Hwi; Suh, Beomseon; Park, Ji Youn; Jeong, Na-rae; Park, Chi Hoon; Ryu, Je Ho; Lee, Byung-Hoon; Kim, Pilho; Lee, Song Hee
Abstract: Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK–expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type–dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell–related blood cancers with improved efficacy and diverse applicability. © 2022 by The American Society of Hematology.
2022-12-31T15:00:00Z
Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1
Chung, Scisung
Kang, Mi-Sun
Alimbetov, Dauren S.
Mun, Gil-Im
Yunn, Na-Oh
Kim, Yunjin
Kim, Byung-Gyu
Wie, Minwoo
Lee, Eun A.
Ra, Jae Sun
Oh, Jung-Min
Lee, Donghyun
Lee, Keondo
Kim, Jihan
Han, Seung Hyun
Kim, Kyong-Tai
Chung, Wan Kyun
Nam, Ki Hyun
Park, Jaehyun
Lee, Byung-Hoon
Kim, Sunghoon
Zhao, Weixing
Ryu, Sung Ho
Lee, Yun-Sil
Myung, Kyungjae
Cho, Yunje
http://hdl.handle.net/20.500.11750/17241
2023-01-12T06:10:20Z
2022-10-31T15:00:00Z
Title: Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1
Author(s): Chung, Scisung; Kang, Mi-Sun; Alimbetov, Dauren S.; Mun, Gil-Im; Yunn, Na-Oh; Kim, Yunjin; Kim, Byung-Gyu; Wie, Minwoo; Lee, Eun A.; Ra, Jae Sun; Oh, Jung-Min; Lee, Donghyun; Lee, Keondo; Kim, Jihan; Han, Seung Hyun; Kim, Kyong-Tai; Chung, Wan Kyun; Nam, Ki Hyun; Park, Jaehyun; Lee, Byung-Hoon; Kim, Sunghoon; Zhao, Weixing; Ryu, Sung Ho; Lee, Yun-Sil; Myung, Kyungjae; Cho, Yunje
Abstract: Aminoacyl-tRNA synthetases (ARSs) have evolved to acquire various additional domains. These domains allow ARSs to communicate with other cellular proteins in order to promote non-translational functions. Vertebrate cytoplasmic isoleucyl-tRNA synthetases (IARS1s) have an uncharacterized unique domain, UNE-I. Here, we present the crystal structure of the chicken IARS1 UNE-I complexed with glutamyl-tRNA synthetase 1 (EARS1). UNE-I consists of tandem ubiquitin regulatory X (UBX) domains that interact with a distinct hairpin loop on EARS1 and protect its neighboring proteins in the multi-synthetase complex from degradation. Phosphomimetic mutation of the two serine residues in the hairpin loop releases IARS1 from the complex. IARS1 interacts with BRCA1 in the nucleus, regulates its stability by inhibiting ubiquitylation via the UBX domains, and controls DNA repair function. © 2022, The Author(s).
2022-10-31T15:00:00Z
Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies
Tran, Non-Nuoc
Lee, Byung-Hoon
http://hdl.handle.net/20.500.11750/16912
2022-11-19T08:40:10Z
2022-08-31T15:00:00Z
Title: Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies
Author(s): Tran, Non-Nuoc; Lee, Byung-Hoon
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which motor neurons in spinal cord and motor cortex are progressively lost. About 15% cases of ALS also develop the frontotemporal dementia (FTD), in which the frontotemporal lobar degeneration (FTLD) occurs in the frontal and temporal lobes of the brain. Among the pathologic commonalities in ALS and FTD is ubiquitin-positive cytoplasmic aggregation of TDP-43 that may reflect both its loss-of-function and gain-of-toxicity from proteostasis impairment. Deep understanding of how protein quality control mechanisms regulate TDP-43 proteinopathies still remains elusive. Recently, a growing body of evidence indicates that ubiquitinating and deubiquitinating pathways are critically engaged in the fate decision of aberrant or pathological TDP-43 proteins. E3 ubiquitin ligases coupled with deubiquitinating enzymes may influence the TDP-43-associated proteotoxicity through diverse events, such as protein stability, translocation, and stress granule or inclusion formation. In this article, we recapitulate our current understanding of how ubiquitinating and deubiquitinating mechanisms can modulate TDP-43 protein quality and its pathogenic nature, thus shedding light on developing targeted therapies for ALS and FTD by harnessing protein degradation machinery.
2022-08-31T15:00:00Z
Allosteric control of Ubp6 and the proteasome via a bidirectional switch
Hung, Ka Ying Sharon
Klumpe, Sven
Eisele, Markus R.
Elsasser, Suzanne
Tian, Geng
Sun, Shuangwu
Moroco, Jamie A.
Cheng, Tat Cheung
Joshi, Tapan
Seibel, Timo
Van Dalen, Duco
Feng, Xin-Hua
Lu, Ying
Ovaa, Huib
Engen, John R.
Lee, Byung-Hoon
Rudack, Till
Sakata, Eri
Finley, Daniel
http://hdl.handle.net/20.500.11750/16455
2022-11-08T18:08:37Z
2022-01-31T15:00:00Z
Title: Allosteric control of Ubp6 and the proteasome via a bidirectional switch
Author(s): Hung, Ka Ying Sharon; Klumpe, Sven; Eisele, Markus R.; Elsasser, Suzanne; Tian, Geng; Sun, Shuangwu; Moroco, Jamie A.; Cheng, Tat Cheung; Joshi, Tapan; Seibel, Timo; Van Dalen, Duco; Feng, Xin-Hua; Lu, Ying; Ovaa, Huib; Engen, John R.; Lee, Byung-Hoon; Rudack, Till; Sakata, Eri; Finley, Daniel
Abstract: The proteasome recognizes ubiquitinated proteins and can also edit ubiquitin marks, allowing substrates to be rejected based on ubiquitin chain topology. In yeast, editing is mediated by deubiquitinating enzyme Ubp6. The proteasome activates Ubp6, whereas Ubp6 inhibits the proteasome through deubiquitination and a noncatalytic effect. Here, we report cryo-EM structures of the proteasome bound to Ubp6, based on which we identify mutants in Ubp6 and proteasome subunit Rpt1 that abrogate Ubp6 activation. The Ubp6 mutations define a conserved region that we term the ILR element. The ILR is found within the BL1 loop, which obstructs the catalytic groove in free Ubp6. Rpt1-ILR interaction opens the groove by rearranging not only BL1 but also a previously undescribed network of three interconnected active-site-blocking loops. Ubp6 activation and noncatalytic proteasome inhibition are linked in that they are eliminated by the same mutations. Ubp6 and ubiquitin together drive proteasomes into a unique conformation associated with proteasome inhibition. Thus, a multicomponent allosteric switch exerts simultaneous control over both Ubp6 and the proteasome. © 2022. The Author(s).
2022-01-31T15:00:00Z