Delving into the Latest Updates on LY-2090314 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GSK-3

Action

inhibitors

Mechanism

GSK-3 inhibitors(Glycogen synthase kinase-3 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesDigestive System Disorders+ [1]

Active Indication-

Inactive Indication

acute leukemiaAdvanced cancerMetastatic Pancreatic Cancer+ [1]

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H25FN6O3

InChIKeyHRJWTAWVFDCTGO-UHFFFAOYSA-N

CAS Registry603288-22-8

The purpose of this study is to determine a recommended Phase 2 dose and dosing regimen of LY2090314 in combination with pemetrexed and carboplatin in patients with advanced/metastatic cancer. Part A of this study will consist of dose escalation of the study regimen, and Part B will consist of an expanded cohort to confirm the dose provided from Part A.

Start Date01 Nov 2007

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with LY-2090314

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100 Translational Medicine associated with LY-2090314

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100 Patents (Medical) associated with LY-2090314

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68

Literatures (Medical) associated with LY-2090314

01 Dec 2024·European Journal of Haematology

A New Strategy for Adult T‐Cell Leukemia Treatment Targeting Glycogen Synthase Kinase‐3β

Article

Author: Ishikawa, Chie ; Mori, Naoki

ABSTRACTObjectivesThe role of glycogen synthase kinase (GSK)‐3β in adult T‐cell leukemia (ATL) caused by human T‐cell leukemia virus type 1 (HTLV‐1) is paradoxical and enigmatic. Here, we investigated the role of GSK‐3β and its potential as a therapeutic target for ATL.MethodsCell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST‐8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK‐3β and cell cycle/death‐related proteins, and survival signals was analyzed using RT‐PCR, immunofluorescence staining, and immunoblotting.ResultsHTLV‐1‐infected T‐cell lines showed nuclear accumulation of GSK‐3β. GSK‐3β knockdown and its inhibition with 9‐ING‐41 and LY2090314 suppressed cell proliferation/survival. 9‐ING‐41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c‐Myc. It induced caspase‐mediated apoptosis by decreasing the expression of Bcl‐xL, Mcl‐1, XIAP, c‐IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9‐ING‐41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis‐derived lactate levels.ConclusionGSK‐3β functions as an oncogene in ATL and could be a potential therapeutic target.

01 Dec 2024·Molecular Diversity

First report on chemometrics-driven multilayered lead prioritization in addressing oxysterol-mediated overexpression of G protein-coupled receptor 183

Article

Author: Kar, Supratik ; Ojha, Probir Kumar ; Bhattacharjee, Arnab

Contemporary research has convincingly demonstrated that upregulation of G protein-coupled receptor 183 (GPR183), orchestrated by its endogenous agonist, 7α,25-dihydroxyxcholesterol (7α,25-OHC), leads to the development of cancer, diabetes, multiple sclerosis, infectious, and inflammatory diseases. A recent study unveiled the cryo-EM structure of 7α,25-OHC bound GPR183 complex, presenting an untapped opportunity for computational exploration of potential GPR183 inhibitors, which served as our inspiration for the current work. A predictive and validated two-dimensional QSAR model using genetic algorithm (GA) and multiple linear regression (MLR) on experimental GPR183 inhibition data was developed. QSAR study highlighted that structural features like dissimilar electronegative atoms, quaternary carbon atoms, and CH₂RX fragment (X: heteroatoms) influence positively, while the existence of oxygen atoms with a topological separation of 3, negatively affects GPR183 inhibitory activity. Post assessment of true external set prediction capability, the MLR model was deployed to screen 12,449 DrugBank compounds, followed by a screening pipeline involving molecular docking, druglikeness, ADMET, protein-ligand stability assessment using deep learning algorithm, molecular dynamics, and molecular mechanics. The current findings strongly evidenced DB05790 as a potential lead for prospective interference of oxysterol-mediated GPR183 overexpression, warranting further in vitro and in vivo validation.

01 Aug 2024·Biomedicine & Pharmacotherapy

Novel selective inhibitors of macropinocytosis-dependent growth in pancreatic ductal carcinoma

Article

Author: Robusto, Michela ; Varasi, Mario ; Mercurio, Ciro ; Frittoli, Emanuela ; Fagá, Giovanni ; Fancelli, Daniele ; Pasi, Maurizio ; Andronache, Adrian ; Dey, Sumit Kumar ; Cera, Maria Rosaria ; Scita, Giorgio ; Brambillasca, Silvia

Macropinocytosis is a cellular process that enables cells to engulf extracellular material, such as nutrients, growth factors, and even whole cells. It is involved in several physiological functions as well as pathological conditions. In cancer cells, macropinocytosis plays a crucial role in promoting tumor growth and survival under nutrient-limited conditions. In particular KRAS mutations have been identified as main drivers of macropinocytosis in pancreatic, breast, and non-small cell lung cancers. We performed a high-content screening to identify inhibitors of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC)-derived cells, aiming to prevent nutrient scavenging of PDAC tumors. The screening campaign was conducted in a well-known pancreatic KRAS-mutated cell line (MIAPaCa-2) cultured under nutrient deprivation and using FITC-dextran to precisely quantify macropinocytosis. We assembled a collection of 3584 small molecules, including drugs approved by the Food and Drug Administration (FDA), drug-like molecules against molecular targets, kinase-targeted compounds, and molecules designed to hamper protein-protein interactions. We identified 28 molecules that inhibited macropinocytosis, with potency ranging from 0.4 to 29.9 μM (EC₅₀). A few of them interfered with other endocytic pathways, while 11 compounds did not and were therefore considered specific "bona fide" macropinocytosis inhibitors and further characterized. Four compounds (Ivermectin, Tyrphostin A9, LY2090314, and Pyrvinium Pamoate) selectively hampered nutrient scavenging in KRAS-mutated cancer cells. Their ability to impair albumin-dependent proliferation was replicated both in different 2D cell culture systems and 3D organotypic models. These findings provide a new set of compounds specifically targeting macropinocytosis, which could have therapeutic applications in cancer and infectious diseases.

100 Deals associated with LY-2090314

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11913

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Pancreatic Cancer	Phase 2	United States	Eli Lilly & Co.	01 Mar 2013
acute leukemia	Phase 2	United States	Eli Lilly & Co.	01 Nov 2010
Advanced cancer	Phase 2	United States	Eli Lilly & Co.	01 Nov 2007
Neoplasm Metastasis	Phase 2	United States	Eli Lilly & Co.	01 Nov 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01632306 (CTgov)	Phase 1/2	Metastatic Pancreatic Cancer	13	gemcitabine+LY2090314 (LY2090314 + Gemcitabine)	(zkuxxhtyup) = vrknxyroaj jiddplkmeu (qehdzngnjr, jveqyhhwsb - tkhgkaonhs) View more	-	19 Nov 2018
				folinic acid+oxaliplatin+LY2090314+fluorouracil (LY2090314 + FOLFOX)	(zkuxxhtyup) = xoamdfqade jiddplkmeu (qehdzngnjr, hkjejrctal - ltfrukwbea) View more
NCT01214603 (CTgov)	Phase 2	acute leukemia	20	LY2090314 (Cohort 1, 40 mg LY2090314: D1, D8, D15)	hkxcylmefo(yuucaymaqz) = mmluqewgjz ngphuyevjf (ellisiwgws, egmlcakovg - qmnstgoesn) View more	-	19 Nov 2018
				LY2090314 (Cohort 2, 40 mg LY2090314: D1, D5, D9)	hkxcylmefo(yuucaymaqz) = epfjxiclik ngphuyevjf (ellisiwgws, xqzqefkdgt - mmsagjlyix) View more
NCT01287520 (Pubmed \| Invest New Drugs) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	78	pemetrexed+carboplatin+LY2090314	(baiduohrni) = nkwoldahkj xljmamtmwt (qsedqqkdox ) View more	Positive	01 Dec 2015