https://scholar.dgist.ac.kr/handle/20.500.11750/1162 2026-09-13T08:28:46Z https://scholar.dgist.ac.kr/handle/20.500.11750/60696 Title: 아이유원 계열의 유비퀴틴 특이적 프로테아제 14 억제제를 유효성분으로 포함하는, 프로탁의 항암 효과 증진용 약학적 조성물 Author(s): 문성현; 이병훈 Abstract: 본 발명은 암의 항암 효과 증진용 약학적 조성물에 관한 것으로서, 보다 구체적으로 탈유비퀴틴화 효소인 USP14를 억제하는 것으로 알려진 IU1 계열 화합물을 포함하는 조성물을 프로탁과 병용하여 투여하는 경우, 프로탁이 가진 암의 예방 또는 치료 효과를 현저하게 증진시키는 것을 확인하였다. 또한, 본 발명의 약학적 조성물을 활용하는 경우, 기존 보다 저용량의 프로탁을 사용하는 경우에도 암을 효과적으로 치료할 수 있어, 독성 및 부작용의 문제에서 자유로울 수 있고, 프로탁의 단독 사용의 경우 발생하는 응용적 한계와 문제점을 개선하여 항암 치료 분야에서 폭넓게 활용될 수 있다. https://scholar.dgist.ac.kr/handle/20.500.11750/58707 Title: PHARMACEUTICAL COMPOSITION COMPRISING IU1-LINEAGE UBIQUITIN-SPECIFIC PROTEASE 14 INHIBITOR AS ACTIVE INGREDIENT FOR ENHANCING ANTICANCER EFFECT OF PROTAC Author(s): 문성현; 이병훈; Tran Thuy Thi Thanh Abstract: The present invention relates to a pharmaceutical composition for enhancing an anticancer effect and, more specifically, identifies that when administered in combination with PROTAC, a composition comprising an IU1-lineage compound, known to inhibit the deubiquitinase USP14, remarkably enhances the prophylactic or therapeutic effect of PROTAC on cancer. In addition, even when PROTAC is used at a lower dose than conventional doses, the utilization of the pharmaceutical composition of the present invention can effectively treat cancer, thus being free from the problems of toxicity and adverse effects. The pharmaceutical composition overcomes the applicative limitations and problems generated upon the use of PROTAC alone and thus can be widely used in the anticancer therapy field. https://scholar.dgist.ac.kr/handle/20.500.11750/57389 Title: Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner Author(s): Lim, Jin Ju; Noh, Sujin; Kang, Woojun; Hyun, Bom; Lee, Byung-Hoon; Hyun, Seogang Abstract: Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis. Abbreviations: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14. © 2024 Informa UK Limited, trading as Taylor & Francis Group. 2024-11-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/56656 Title: Structural Dynamics Analysis of USP14 Activation by AKT-Mediated Phosphorylation Author(s): Dash, Raju; Tran, Non-Nuoc; Lee, Sung Bae; Lee, Byung-Hoon Abstract: Ubiquitin-specific protease 14 (USP14), one of the three major proteasome-associated deubiquitinating enzymes (DUBs), is known to be activated by the AKT-mediated phosphorylation at Ser432. Thereby, AKT can regulate global protein degradation by controlling the ubiquitin-proteasome system (UPS). However, the exact molecular mechanism of USP14 activation by AKT phosphorylation at the atomic level remains unknown. By performing the molecular dynamics (MD) simulation of the USP14 catalytic domain at three different states (inactive, active, and USP14-ubiquitin complex), we characterized the change in structural dynamics by phosphorylation. We observed that the Ser432 phosphorylation induced substantial conformational changes of USP14 in the blocking loop (BL) region to fold it from an open loop into a β-sheet, which is critical for USP14 activation. Furthermore, phosphorylation also increased the frequency of critical hydrogen bonding and salt bridge interactions between USP14 and ubiquitin, which is essential for DUB activity. Structural dynamics insights from this study pinpoint the important local conformational landscape of USP14 by the phosphorylation event, which would be critical for understanding USP14-mediated proteasome regulation and designing future therapeutics. © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 2024-05-31T15:00:00Z