Delving into the Latest Updates on BIIB-021 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BIIB021

+ [2]

Target

HSP90 x HSP90B

Action

inhibitors

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors), HSP90B inhibitors(Heat shock protein HSP 90-beta inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersSkin and Musculoskeletal Diseases+ [3]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmChronic Lymphocytic LeukemiaGastrointestinal Stromal Tumors+ [4]

Originator Organization

Biogen, Inc.

Active Organization-

Inactive Organization

Biogen, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC15H19ClN6O4S

InChIKeyQQYUAUPJJLOCHU-UHFFFAOYSA-N

CAS Registry1225041-97-3

View All Structures (2)

CONTEXTHeat-shock proteins (HSPs), particularly HSP90, are critical molecular chaperones that maintain protein stability, especially in cancer cells. Elevated HSP90 levels in tumors aid in oncogenic protein stabilization. This study focuses on developing potent, selective HSP90 inhibitors to disrupt its chaperone function, targeting cancer cell survival. Using a de novo hybridization approach, we designed novel inhibitors by integrating structural fragments from a known HSP90-binding drug, leading to the creation of hybrid compounds C1, C2, and C3. A 300 ns molecular dynamics simulation of each system revealed that C1, C2, and C3 formed more stable complexes with HSP90 compared to the reference compound, MEY. RMSD, RMSF, Rg, SASA, and MM-PBSA metrics supported these findings. DCCM and FEL analyses confirmed that the inhibitors did not alter HSP90's initial configuration. Further DFT calculations with the B3LYP/6-311 + + (d,p) basis set were conducted to evaluate frontier molecular orbitals, MEP surfaces, ELF, LOL maps, TDOS and PDOS. The results indicated that C1, C2, and C3 formed more stable complexes with HSP90 compared to the reference compound MEY. These findings affirm the potential of C1, C2, and C3 as new anti-cancer therapies. Our approach demonstrates a promising strategy for developing selective HSP90 inhibitors that maintain the protein's functional integrity while disrupting its oncogenic role, paving the way for further preclinical evaluation of these novel compounds.METHODSMaestro 11.8, Discovery Studio Visualizer, Gromacs-2023, Gaussian 16, and online platforms like SwissADME and ProTox-II were utilized. Fragments generated from eight known HSP90-binding drugs were subjected to SP-docking, leading to 170 fragments. The highest-scoring fragments were merged using the breed panel to create new HSP90 inhibitors. XP-docking and ADMET analyses identified C1, C2, and C3 as the most promising candidates. These compounds were selected for a 300 ns dynamic simulation and subsequent DFT calculations.

26 Sep 2024·Journal of Medicinal Chemistry

Heat Shock Protein 90 Interactome-Mediated Proteolysis Targeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4 to Trigger Ferroptosis

Article

Author: Dong, Jinyun ; Cao, Fei ; Cheng, Xiangdong ; Ding, Guangyu ; Ma, Furong ; Li, Haobin ; Li, Juan ; Liang, Hui ; Cai, Maohua ; Qin, Jiang-Jiang ; Li, Yulong

Targeted protein degradation (TPD) is an emerging therapeutic paradigm aimed at eliminating the disease-causing protein with aberrant expression. Herein, we report a new approach to inducing intracellular glutathione peroxidase 4 (GPX4) protein degradation to trigger ferroptosis by bridging the target protein to heat shock protein 90 (HSP90), termed HSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC). Different series of HIM-PROTACs were synthesized and evaluated, and two of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated ubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC₅₀ values of 0.18 and 0.08 μM, respectively. In particular, GDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor ML162. Moreover, these two degraders effectively suppress tumor growth in the mice model with relatively low toxicity as compared to the combination therapy of GPX4 and HSP90 inhibitors. In general, this study demonstrated the feasibility of degrading GPX4 via HSP90 interactome, and thus provided a significant complement to existing TPD strategies.

01 Jul 2024·Naunyn-Schmiedeberg's Archives of Pharmacology

Molecular mechanism of anticancer effect of heat shock protein 90 inhibitor BIIB021 in human bladder cancer cell line

Article

Author: Özgür, Aykut ; Asdemir, Aydemir

AbstractBladder cancer is a type of urologic malignancy that exhibits significant morbidity, mortality, and treatment costs. Inhibition of heat shock protein 90 (HSP90) activity has been a promising pharmacological strategy for blocking of bladder cancer pathogenesis. BIIB021 is a next-generation HSP90 inhibitor which interrupts ATP hydrolysis process of HSP90 and inhibits the stabilization and correct folding of client proteins. In current study, we aimed to investigate the molecular mechanism of the anticancer activity of BIIB021 in human bladder cancer T24 cells. Our results revealed that nanomolar concentration of BIIB021 decreased viability of T24 cell. BIIB021 downregulated HSP90 expression in T24 cells and inhibited the refolding activity of luciferase in the presence of T24 cell lysate. PCR array data indicated a significant alteration in transcript levels of cancer-related genes involved in metastases, apoptotic cell death, cell cycle, cellular senescence, DNA damage and repair mechanisms, epithelial-to-mesenchymal transition, hypoxia, telomeres and telomerase, and cancer metabolism pathways in T24 cells. All findings hypothesize that BIIB021 could exhibit as effective HSP90 inhibitor in the future for treatment of bladder cancer patients.

100 Deals associated with BIIB-021

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12359

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hormone receptor positive breast cancer	Phase 2	Russia	Biogen, Inc.	01 Nov 2009
Hormone receptor positive breast cancer	Phase 2	Australia	Biogen, Inc.	01 Nov 2009
Hormone receptor positive breast cancer	Phase 2	Belgium	Biogen, Inc.	01 Nov 2009
Hormone receptor positive breast cancer	Phase 2	United States	Biogen, Inc.	01 Nov 2009
Gastrointestinal Stromal Tumors	Phase 2	United States	Biogen, Inc.	01 Feb 2008
Advanced Malignant Solid Neoplasm	Phase 2	United States	Biogen, Inc.	01 Feb 2006
Advanced Malignant Solid Neoplasm	Phase 2	United Kingdom	Biogen, Inc.	01 Feb 2006
Chronic Lymphocytic Leukemia	Phase 2	United States	Biogen, Inc.	01 Feb 2006
Lymphoma	Phase 2	United States	Biogen, Inc.	01 Feb 2006
Lymphoma	Phase 2	United Kingdom	Biogen, Inc.	01 Feb 2006