Delving into the Latest Updates on Dactolisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Dactolisib (USAN/INN), Dactolisib-tosylate

+ [5]

Target

PI3K family x mTOR

Mechanism

PI3K family inhibitors(Phosphatidylinositol 3-kinase family inhibitors), mTOR inhibitors(Serine/threonine-protein kinase mTOR inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory DiseasesNervous System Diseases+ [1]

Active Indication

COVID-19Parkinson Disease

Inactive Indication

Advanced breast cancerAdvanced Endometrial CarcinomaAdvanced Malignant Solid Neoplasm+ [16]

Originator Organization

Novartis Pharma AG

Active Organization

resTORbio, Inc.

Inactive Organization

Novartis Pharmaceuticals Corp.

Pfizer Inc.

Novartis AG

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC30H23N5O

InChIKeyJOGKUKXHTYWRGZ-UHFFFAOYSA-N

CAS Registry915019-65-7

Background:Stomach adenocarcinoma (STAD) is the fifth most common tumor worldwide, imposing a significant disease burden on populations, particularly in Asia. Oxidative stress is well-known to play an essential role in the occurrence and progression of malignancies. Our study aimed to construct a prediction model by exploring the correlation between oxidative stress-related genes and the prognosis of patients with STAD.Method:STAD data from TCGA were used to identify the differentially expressed oxidative stress-related genes (OSGs), with data from GEO serving as the validation cohort. Univariate Cox and LASSO regression analyses were performed to select prognosis-related genes for the risk model, which was then integrated with clinical features into a nomogram. The physiological functions and pathways of these identified genes were explored using GO and KEGG analyses. After evaluating the prediction value of the prognostic model in the GEO cohort, drug sensitivity and immune infiltration were comprehensively analyzed using R. Expression levels of the prognostic genes were verified by quantitative real-time PCR in gastric cancer and paired normal tissues.Results:Cox regression and LASSO regression analysis identified SERPINE1, VHL, CD36, NOS3, ANXA5, ADCYAP1, POLRMT and GPX3 as the signature genes from 160 differentially expressed OSGs. Both Kaplan–Meier survival analysis and ROC curve at 5 years in the TCGA and the GEO cohort exhibited great predictive ability of the prognostic model, with the AUC >0.7 in TCGA. Validated as an independent risk factor, the model was integrated with clinicopathological variables (including age, stage, and gender) to build a nomogram for more accurate risk stratification. Moreover, therapy sensitivity analysis between the low- and high-risk categories showed that those who scored higher would benefit more from BEZ235, Dasatinib, Pazopanib, and Saracatinib. Meanwhile, differences in the tumor environment, immune infiltration and response to immunotherapy between the two groups were noted. Finally, qRT-PCR validated the differential expression of these genes in STAD and paired normal tissues.Conclusion:Our study has effectively established an oxidative stress-related prognostic model, providing a promising tool for personalized clinical strategies and improved STAD patient outcomes.

31 Dec 2024·Cancer Biology & Therapy

Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma

Article

Author: Wang, Han-Wei ; Liu, Feng ; Liu, Shan-Ling ; Wang, Xiao-Yang ; Liu, Zhen ; Guo, Ying ; Gao, Feng-Hou ; Zhang, Chao

BACKGROUNDCDK4 is highly expressed and associated with poor prognosis and decreased survival in advanced neuroblastoma (NB). Targeting CDK4 degradation presents a potentially promising therapeutic strategy compared to conventional CDK4 inhibitors. However, the autophagic degradation of the CDK4 protein and its anti-proliferation effect in NB cells has not been mentioned.RESULTSWe identified autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest, as demonstrated by the overexpression of CDK4, autophagy inhibition, and blockade of autophagy-related genes. Secondly, we present the first evidence that p62 binds to CDK4 and then enters the autophagy-lysosome to degrade CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model.CONCLUSIONSAutophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.

01 Dec 2024·Molecular Biology Reports

Protein kinase C iota promotes glycolysis via PI3K/AKT/mTOR signalling in high grade serous ovarian cancer

Article

Author: Roy, Adhiraj ; Mandal, Supratim ; Tyagi, Komal

BACKGROUNDEpithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation.METHODS AND RESULTSTwo high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC.CONCLUSIONTaken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.

100 Deals associated with Dactolisib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10552	Dactolisib	-	DB11651

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Tract Infections	Phase 2	NZ	resTORbio, Inc.	15 Apr 2019
Locally advanced breast cancer	Phase 2	FR	Novartis Pharmaceuticals Corp.	30 Jan 2012
Locally advanced breast cancer	Phase 2	ES	Novartis Pharmaceuticals Corp.	30 Jan 2012
Locally advanced breast cancer	Phase 2	ES	Novartis Pharmaceuticals Corp.	30 Jan 2012
Metastatic breast cancer	Phase 2	FR	Novartis Pharmaceuticals Corp.	30 Jan 2012
Metastatic breast cancer	Phase 2	ES	Novartis Pharmaceuticals Corp.	30 Jan 2012
Advanced Renal Cell Carcinoma	Phase 2	US	Novartis AG	01 Oct 2011
Locally advanced breast cancer	Phase 1	FR	Novartis Pharmaceuticals Corp.	30 Jan 2012
Metastatic breast cancer	Phase 1	FR	Novartis Pharmaceuticals Corp.	30 Jan 2012
Respiratory Tract Infections	Preclinical	NZ	resTORbio, Inc.	15 Apr 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04668352 (CTgov)	Phase 3	Respiratory Tract Infections	1,024	Placebo (Placebo)	qubgggvkze(fhnnyftaku) = ttyvvmsugc undcayovpb (ceskmwypih, cclnxbbcqz - ambrsbohma) View more	-	23 Jun 2021
				Dactolisib (Dactolisib 10mg Once Daily)	qubgggvkze(fhnnyftaku) = igjyrekzww undcayovpb (ceskmwypih, rwsjjwibtg - uperjhiaeo) View more
NCT01756118 (Pubmed \| BMC Pharmacol Toxicol) Manual	Phase 1	acute leukemia	24	BEZ235	(otkkhlivet) = ejnruuamot lnqbsopbxj (asdypixwtu ) View more	Negative	29 Sep 2020
NCT01195376 (Pubmed \| Cancer Chemother Pharmacol)	Phase 1	Advanced Malignant Solid Neoplasm	35	BEZ235	(hkvjdftsmz) = lqmqdhgdkq gnpvxunpwd (ukqfyipbdz )	-	01 Feb 2019
NCT01628913 (Pubmed \| Oncologist) Manual	Phase 2	Neuroendocrine Tumors	62	BEZ235	(jasxsxthll) = chsyfqiaop zpfgywbsnk (nkdouxhczb, 5.3 - NE)	Negative	01 Jul 2018
				Everolimus	(jasxsxthll) = vfkzeihnbr zpfgywbsnk (nkdouxhczb, 8.1 - NE)
NCT01717898 (Pubmed \| Oncologist) Manual	Phase 1	Metastatic castration-resistant prostate cancer	6	abiraterone acetate+BEZ235	(prbeyngfwo) = aucffikapx akiawoxviu (qnxqtzkndi ) View more	Negative	01 May 2017
NCT01453595 (Pubmed \| Oncologist) Manual	Phase 1	Advanced Renal Cell Carcinoma	10	BEZ235	(tdqrgxotrh) = msaptoqqmg hbdiqcfler (hywuyzgogi ) View more	Negative	01 Jul 2016
NCT01658436 (CTgov)	Phase 2	Well Differentiated Pancreatic Endocrine Tumor \| Advanced Pancreatic Neuroendocrine Tumor	31	BEZ235 (BEZ235 300 mg/400 mg Bid)	jrswrrzyjh(qypyyvuqng) = nnnxdiksih kepdsyqwad (iacweuhgft, zvjxazrryt - aqeacwotrs) View more	-	02 May 2016
				BEZ235 (BEZ235 300 mg Bid)	muurpgpynq(xvoeqdeajz) = zxtbtsxxxr uzwgosnczh (qjqrlefqiu, yfubvqbdnh - kmxopsxlvd) View more
NCT01628913 (CTgov)	Phase 2	Well Differentiated Pancreatic Endocrine Tumor \| Islet Cell Carcinoma	62	BEZ235 (BEZ235)	(jenbtjetlz) = rfibnuvzji fqvtcgifuo (fimctxlwvk, flqcmoalob - mbpgtxkdes) View more	-	07 Apr 2016
				everolimus (Everolimus)	(jenbtjetlz) = noywxkxevu fqvtcgifuo (fimctxlwvk, gvpcmfqsvp - mnmoptyduo) View more
NCT01453595 (CTgov)	Phase 1/2	Advanced Renal Cell Carcinoma	10	BEZ235 (Cohort -1: BEZ235 200mg)	(plluwcicoi) = ggoontgrvm xlkxitidif (jpdpvdsyqj, pnxwptvwbr - elmoiceogg) View more	-	29 Feb 2016
				BEZ235 (Cohort 1: BEZ235 400mg)	nfunzilhpq(ehollapctw) = fuhuohpeaj nuhyfamopq (baeztobkbk, ifottpvass - nbjffoklwk) View more
NCT01658436 (Pubmed) Manual	Phase 2	Neuroendocrine Tumors	31	BEZ235 (400 mg daily)	(lfddpmajag) = lnhjrvarpw uhbnrxqswt (crsnxfpqif )	Negative	01 Feb 2016
				BEZ235 (300 mg daily)	(lfddpmajag) = yfectfozap uhbnrxqswt (crsnxfpqif )