MAP4K2 inhibitors(mitogen-activated protein kinase kinase kinase kinase 2 inhibitors), RB1 modulators(RB transcriptional corepressor 1 modulators), Syk inhibitors(Spleen tyrosine kinase inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesInfectious Diseases+ [3]

Active Indication

Multiple MyelomaAnaphylaxisRespiratory tract inflammation

Inactive Indication

Retinoblastoma

Originator Organization

St. Jude Children's Research Hospital, Inc.

Active Organization

Columbia University Irving Medical Center

Bayer AG

Inactive Organization

St. Jude Children's Research Hospital, Inc.

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC20H20Cl2N6O3

InChIKeySPMFEULFGGPQLN-UHFFFAOYSA-N

CAS Registry648903-57-5

100 Clinical Results associated with BAY 61-3606

100 Translational Medicine associated with BAY 61-3606

100 Patents (Medical) associated with BAY 61-3606

Literatures (Medical) associated with BAY 61-3606

01 Oct 2024·Neurobiology of Disease

Syk inhibitors reduce tau protein phosphorylation and oligomerization

Article

Author: Asano, Rei ; Sada, Kiyonao ; Kitazaki, Yuki ; Nakamoto, Yasunari ; Murayama, Shigeo ; Ikawa, Masamichi ; Hamano, Tadanori ; Sasaki, Hirohito ; Yamaguchi, Tomohisa ; Kanaan, Nicholas M ; Endo, Yoshinori ; Fujita, Youshi ; Yen, Shu-Hui ; Yamamura, Osamu ; Shirafuji, Norimichi ; Aoki, Koji ; Morishima, Maho ; Naiki, Hironobu ; Enomoto, Soichi ; Saito, Yuko ; Kanaan, Nicholas M.

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors-BAY 61-3606 and R406-on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.

12 Dec 2023·Journal of Biomolecular Structure and Dynamics

Insights into molecular docking and dynamics to reveal therapeutic potential of natural compounds against P53 protein

Article

Author: Maqbool, Irfan ; Alsaffar, Rana M. ; Rehman, Muneeb U. ; Malla, Bashir Ahmad ; Ahmad, Sheikh Bilal ; Ali, Aarif ; Dar, Nazir Ahmad

P53 is eminent tumour suppressor protein that plays a prominent role in cell cycle arrest, DNA repair, senescence, differentiation and initiation of apoptosis. P53 is an attractive drug target and the high toxicity of some cancer chemotherapy drugs increase the demand for new anti-cancer drugs from natural products. In this current scenario, identification of promising anticancer compounds from natural sources by repurposing approach is still relevant for the early prevention and effective management of cancer. In present study, we docked natural compounds like podophyllotoxin, quercetin and rutin along standard drugs (MG-132 and Bay 61-3606) against p53 protein. ADME/T analysis predicted toxicity of phytochemicals and drugs. In silico docking analysis of podophyllotoxin, quercetin and rutin gave HDOCK docking scores of -187.87, -148. 97 and -143.85, whereas control drugs MG-132 and Bay 61-3606 showed docking scores of -159.59 and -140.71 against p53 respectively. AutoDock analysis of rutin and MG-132 showed highest binding affinity scores of -7.3 and -6.8 kcal/mol against p53. Molecular dynamic simulation for p53 protein displayed stable conformation and convergence. In this study, P53-rutin complex showed free binding energy score of 11.84 kcal/mol and P53-MG-132 complex reported free energy score of 16.3 kcal/mol. Protein contacts atlas gives non-covalent contacts framework by exploring interfaces of individual subunits and protein-ligand interactions. STRING tool predicts physical and functional interactions between proteins. The results of this study revealed that rutin and MG-132 could be promising inhibitors against targeted p53 protein and this could prove detrimental for molecular therapeutics and drug-designing strategies.Communicated by Ramaswamy H. Sarma.

01 May 2023·The Journal of Pathology: Clinical Research

Low gamma‐butyrobetaine dioxygenase (BBOX1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma: a machine learning approach

Article

Author: Lee, Seung Wook ; Shin, Su-Jin ; Kim, Kyu-Shik ; Kwon, Mi Jung ; Moon, Kyoung Min ; Oh, Sukjoong ; Kim, Dong-Hoon ; Min, Kyueng-Whan ; Jung, Woon Yong ; Noh, Yung-Kyun

AbstractGamma‐butyrobetaine dioxygenase (BBOX1) is a catalyst for the conversion of gamma‐butyrobetaine to l‐carnitine, which is detected in normal renal tubules. The purpose of this study was to analyze the prognosis, immune response, and genetic alterations associated with low BBOX1 expression in patients with clear cell renal cell carcinoma (RCC). We analyzed the relative influence of BBOX1 on survival using machine learning and investigated drugs that can inhibit renal cancer cells with low BBOX1 expression. We analyzed clinicopathologic factors, survival rates, immune profiles, and gene sets according to BBOX1 expression in a total of 857 patients with kidney cancer from the Hanyang University Hospital cohort (247 cases) and The Cancer Genome Atlas (610 cases). We employed immunohistochemical staining, gene set enrichment analysis, in silico cytometry, pathway network analyses, in vitro drug screening, and gradient boosting machines. BBOX1 expression in RCC was decreased compared with that in normal tissues. Low BBOX1 expression was associated with poor prognosis, decreased CD8+ T cells, and increased neutrophils. In gene set enrichment analyses, low BBOX1 expression was related to gene sets with oncogenic activity and a weak immune response. In pathway network analysis, BBOX1 was linked to regulation of various T cells and programmed death‐ligand 1. In vitro drug screening showed that midostaurin, BAY‐61‐3606, GSK690693, and linifanib inhibited the growth of RCC cells with low BBOX1 expression. Low BBOX1 expression in patients with RCC is related to short survival time and reduced CD8+ T cells; midostaurin, among other drugs, may have enhanced therapeutic effects in this context.

100 Deals associated with BAY 61-3606

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Preclinical	United States	Columbia University Irving Medical Center	29 Nov 2018
Retinoblastoma	Preclinical	United States	St. Jude Children's Research Hospital, Inc.	11 Jan 2012
Anaphylaxis	Preclinical	Germany	Bayer AG	23 May 2003
Respiratory tract inflammation	Preclinical	Germany	Bayer AG	23 May 2003

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