Delving into the Latest Updates on Litronesib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Litronesib (USAN/INN)

+ [2]

Target

KIF11

Action

inhibitors

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [4]

Active Indication-

Inactive Indication

acute leukemiaAdvanced cancerColorectal Cancer+ [9]

Originator Organization

Kyowa Kirin Co., Ltd.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Kyowa Kirin Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H37N5O4S2

InChIKeyYVAFBXLHPINSIK-QHCPKHFHSA-N

CAS Registry910634-41-2

AbstractLung adenocarcinoma (LUAD) is a major subtype of non‐small‐cell lung cancer and accompanies high mortality rates. While the role of bilirubin metabolism in cancer is recognized, its specific impact on LUAD and patient response to immunotherapy needs to be elucidated. This study aimed to develop a prognostic signature of bilirubin metabolism‐associated genes (BMAGs) to predict outcomes and efficacy of immunotherapy in LUAD. We analysed gene expression data from The Cancer Genome Atlas (TCGA) to identify survival‐related BMAGs and construct a prognostic model in LUAD. The prognostic efficacy of our model was corroborated by employing TCGA‐LUAD and five Gene Expression Omnibus datasets, effectively stratifying patients into risk‐defined cohorts with marked disparities in survival. The BMAG signature was indeed an independent prognostic determinant, outperforming established clinical parameters. The low‐risk group exhibited a more favourable response to immunotherapy, highlighted by increased immune checkpoint expression and immune cell infiltration. Further, somatic mutation profiling differentiated the molecular landscapes of the risk categories. Our screening further identified potential drug candidates preferentially targeting the high‐risk group. Our analysis of critical BMAGs showed the tumour‐suppressive role of FBP1, highlighting its suppression in LUAD and its inhibitory effects on tumour proliferation, migration and invasion, in addition to its involvement in cell cycle and apoptosis regulation. These findings introduce a potent BMAG‐based prognostic indicator and offer valuable insights for prognostication and tailored immunotherapy in LUAD.

01 Aug 2022·Anti-Cancer Agents in Medicinal ChemistryQ4 · MEDICINE

Role of KSP Inhibitors as Anti-Cancer Therapeutics: An Update

Q4 · MEDICINE

Review

Author: Suvarna, Vasanti ; Chamariya, Rinkal

Abstract:Regardless of the growing discovery of anticancer treatments targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance because tumours harbor a greater population of actively dividing cells than normal tissues. Conventional anti-mitotic agents or microtubule poisons acting on the major mitotic spindle protein tubulin have been effectively used in clinical settings for cancer chemotherapy over the last three decades. However, the use of these drugs is associated with limited clinical utility due to serious side effects such as debilitating and dose-limiting peripheral neuropathy, myelosuppression, drug resistance, and allergic reactions. Therefore, research initiatives have been undertaken to develop novel microtubule motor proteins inhibitors that can potentially circumvent the limitations associated with conventional microtubule poisons. Kinesin spindle proteins (KSP) belonging to the kinesin-5 family play a crucial role during mitosis and unregulated cell proliferation. Evidence from preclinical studies and different phases of clinical trials have presented kinesin spindle protein as a promising target for cancer therapeutics. Kinesin spindle protein inhibitors causing mitosis disruption without interfering with microtubule dynamics in non-dividing cells offer a potential therapeutic alternative for the management of several major cancer types and are devoid of side effects associated with classical anti-mitotic drugs. This review summarizes recent data highlighting progress in the discovery of targeted KSP inhibitors and presents the development of scaffolds, structure-activity relationships, and outcomes of biological and enzyme inhibition studies. We reviewed the recent literature reports published over the last decade, using various electronic database searches such as PubMed, Embase, Medline, Web of Science, and Google Scholar. Clinical trial data till 2021 was retrieved from ClinicalTrial.gov. Major chemical classes developed as selective KSP inhibitors include dihydropyrimidines, β-carbolines, carbazoles, benzimidazoles, fused aryl derivatives, pyrimidines, fused pyrimidines, quinazolines, quinolones, thiadiazolines, spiropyran, and azobenzenes. Drugs such as filanesib, litronesib, ispinesib have entered clinical trials; the most advanced phase explored is Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.

01 Jul 2022·Translational Cancer Research

Novel hypoxia features with appealing implications in discriminating the prognosis, immune escape and drug responses of 947 hepatocellular carcinoma patients

Article

Author: Si, Hongzong ; Luan, Mingyuan

BackgroundHypoxia has a profound impact on the development and progression of hepatocellular carcinoma (HCC). This study aimed to explore and elucidate how hypoxia affect prognosis, immune escape and drug responses in HCC.MethodsHCC-specific hypoxia signatures were identified based on the intersect of differentially expressed genes (DEGs) of GSE41666 and GSE15366. The hypoxia score was calculated using the gene set variation analysis (GSVA) function and validated on GSE18494. We collected five cohorts [The Cancer Genome Atlas (TCGA), GSE14520, GSE39791, GSE36376, GSE57957] for further analysis. First, we analyzed the effect of the hypoxia score on prognosis. Next, we systematically analyzed the potential hypoxia-related immune escape mechanisms and the effect of hypoxia upon immunotherapy. Then, we predicted and screened potential sensitive drugs for HCC patients with high hypoxia levels using machine learning and docking.ResultsWe constructed a novel HCC-specific hypoxia score and undertook further analysis in five cohorts (TCGA, GSE14520, GSE39791, GSE36376, GSE57957). We observed that patients with high hypoxia scores exhibited worse overall survival (OS) in TCGA and GSE14520. We also constructed a hypoxia-related nomogram that had good performance in predicting HCC patients' prognosis. Furthermore, patients with lower hypoxia scores had a lower risk of immune escape and thus may benefit from immunotherapy. Finally, we predicted and screened VLX600 as the candidate drug for HCC patients with high hypoxia scores. We further explored and elucidated why VLX600 was more sensitive in HCC patients with high hypoxia than with low hypoxia HCC patients using weighted gene co-expression network analysis (WGCNA).ConclusionsThis study provides further evidence of the link between hypoxia and prognosis and immune escape in HCC patients. Moreover, our research screened VLX600 as a potential drug for HCC patients with high hypoxia levels and elucidated the potential mechanism.

100 Deals associated with Litronesib

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External Link

KEGG	Wiki	ATC	Drug Bank
D09636	-	-	DB11861

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Esophageal Carcinoma	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Non-Small Cell Lung Cancer	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Ovarian Cancer	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Prostatic Cancer	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Squamous Cell Carcinoma of Head and Neck	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Stomach Cancer	Phase 2	United States	Eli Lilly & Co.	01 Apr 2011
Extensive stage Small Cell Lung Cancer	Phase 2	United States	Eli Lilly & Co.	01 Dec 2009
Extensive stage Small Cell Lung Cancer	Phase 2	Romania	Eli Lilly & Co.	01 Dec 2009
Extensive stage Small Cell Lung Cancer	Phase 2	South Korea	Eli Lilly & Co.	01 Dec 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01025284 (CTgov)	Phase 2	Extensive stage Small Cell Lung Cancer	64	LY2523355 (Part A)	pfrmzkzqjf(qkpbilfxuy) = jezzqybeup gbfkiufdfe (mjgufrdqiz, qfrmvbbusa - vfwhfryhoz) View more	-	04 Dec 2017
				granulocyte colony-stimulating factor (G-CSF)+LY2523355 (Part B)	ykhzjdbtxl(kzyaxsohsh) = fnhbzadcgg qccycgrsdo (pesxbdsydb, lrfyddadbr - ylbwhkjjmy) View more
NCT01059643 (CTgov)	Phase 2	Ovarian Cancer \| Esophageal Carcinoma \| Squamous Cell Carcinoma of Head and Neck \| Non-Small Cell Lung Cancer \| Prostatic Cancer \| Colorectal Cancer \| Stomach Cancer	103	pegfilgrastim+LY2523355	nzlwdyjerx(tgufcrncua) = cufwpcopoi eitqulvpdp (fypgzayxec, cxqedhywri - ldyjtovgpo) View more	-	04 Dec 2017
NCT01416389 (CTgov)	Phase 2	Metastatic breast cancer	39	pegfilgrastim+LY2523355+filgrastim (LY2523355 + Pegfilgrastim or Filgrastim)	kqpbpuakxk(vnnfjucred) = zrgidcmndc gsljnuqxvb (gfwwuossvf, xiqqrkukwd - mivymhlphk) View more	-	04 Dec 2017
				ixabepilone (Ixabepilone)	kqpbpuakxk(vnnfjucred) = qpwuwbdjln gsljnuqxvb (gfwwuossvf, qpzmjuapkr - eyxdiuzctm) View more
NCT01214642 (Pubmed \| Cancer Chemother Pharmacol) Manual	Phase 1	Advanced cancer	117	litronesib	(nmjmpcewgo) = 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. xrbgwdmzba (squvbtxhpy ) View more	Positive	01 Feb 2017
				litronesib+pegfilgrastim