PXD046016-1

PXD046016 is an original dataset announced via ProteomeXchange.

Title	NAMPT-targeting PROTAC and nicotinic acid co-administration elicits safe and robust anti-tumor efficacy in NAPRT-deficient pan-cancers
Description	Nicotinamide phosphoribosyltransferase (NAMPT) serves as the key enzyme in the salvage pathway-mediated biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. However, two significant challenges hinder its successful translation to clinical usage. Firstly, the targeting of the extracellular form of NAMPT (eNAMPT) remains insufficient. Secondly, there are considerable side effects observed in normal tissues, particularly in the hematopoietic system, which relies heavily on the salvage pathway for NAD+ production. In previous research, we utilized proteolysis-targeting chimera (PROTAC) technology to develop two compounds (SIAIS630120 and SIAIS630121) capable of simultaneously degrading iNAMPT and eNAMPT proteins. Unfortunately, the pharmacokinetic properties of these compounds were inadequate for clinical investigation, and toxicity concerns similar to those associated with traditional inhibitors arose. To address these challenges, we have developed a next-generation PROTAC molecule 632005 that demonstrates exceptional target selectivity and bioavailability. This molecule boasts improved in vivo exposure, extended half-life, and reduced clearance rate, positioning it as a highly promising candidate for future clinical applications. Moreover, when combined with nicotinic acid, 632005 successfully exhibits both safety and robust efficacy in the treatment of NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and PDX models with liver cancer. Our findings provide crucial references for patient selection and treatment strategies involving NAMPT-targeting PROTACs in a clinical setting.
HostingRepository	iProX
AnnounceDate	2023-10-10
AnnouncementXML	Submission_2023-10-10_00:20:21.242.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaotong Zhu
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-10 00:20:13	ID requested
⏵ 1	2023-10-10 00:20:21	announced

Dataset with its publication pending

submitter keyword: NAMPT, PROTAC, Synthetic lethal, NAPRT, Nicotinic acid

Gaofeng Fan
contact affiliation	ShanghaiTech University
contact email	fangf@shanghaitech.edu.cn
lab head
Xiaotong Zhu
contact affiliation	ShanghaiTech University
contact email	834988204@qq.com
dataset submitter

iProX dataset URI