Name: Nirogacestat (PF-03084014)
Brand: Selleck Chemicals
SKU: S8018
Rating: 5 (21 reviews)

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품질 관리 (Quality Control)

배치: 순도: 99.31%

99.31

관련 타겟	HDAC Caspase Proteasome MMP HCV Protease Cysteine Protease Tyrosinase HIV Protease DPP Serine Protease
기타 Secretase 억제제	DAPT RO4929097 (RG-4733) LY411575 Dibenzazepine (YO-01027) MK-0752 Avagacestat (BMS-708163) Semagacestat (LY450139) MDL-28170 L-685,458 NGP 555

화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량	489.64	화학식	C₂₇H₄₁F₂N₅O	보관 (수령일로부터)	3년-20°C분말
CAS 번호	1290543-63-3	SDF 다운로드		원액 보관	1년-80°C용매에 보관 1개월-20°C용매에 보관
동의어	PF-3084014			Smiles	CCCC(C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C)NC2CCC3=C(C2)C(=CC(=C3)F)F

용해도 (Solubility)

In vitro
배치:

DMSO : 98 mg/mL (200.14 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 49 mg/mL

Water : Insoluble

DMSO : 98 mg/mL (200.14 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 98 mg/mL

Water : Insoluble

DMSO : 97 mg/mL (198.1 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 97 mg/mL

Water : Insoluble

DMSO : 97 mg/mL (198.1 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 97 mg/mL

Water : Insoluble

DMSO : 97 mg/mL (198.1 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 97 mg/mL

Water : Insoluble

몰농도 계산기

질량	농도	부피	분자량
=	×	×

희석 계산기 분자량 계산기

In vivo 배치:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Selleck 연구소에서 검증되었습니다. 이 제형에 대한 조정이 필요한 경우 맞춤 테스트를 위해 당사 영업팀에 문의하십시오.	2.400mg/ml (4.90mM)	Taking the 1 mL working solution as an example, add 50 μL of 48 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

생체 내 제형 계산기 (투명한 용액)

1단계: 아래 정보 입력 (권장: 실험 중 손실을 고려하여 추가 동물 포함)

투여량: mg/kg 동물 평균 체중: g 동물당 투여량:μL 동물 수:

2단계: 생체 내 제형 입력 (이것은 계산기일 뿐 제형이 아닙니다. 용해도 섹션에 생체 내 제형이 없는 경우 먼저 당사에 문의하십시오.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

계산 결과:

작업 농도: mg/ml;

DMSO 원액 준비 방법: mg 약물 사전 용해 μL DMSO ( 원액 농도 mg/mL, 농도가 해당 약물 배치의 DMSO 용해도를 초과하는 경우 먼저 당사에 문의하십시오. )

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가μL PEG300, 혼합하고 투명하게 한 다음 추가μL Tween 80, 혼합하고 투명하게 한 다음 추가 μL ddH₂O, 혼합하고 투명하게 합니다.

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가 μL 옥수수 기름, 혼합하고 투명하게 합니다.

참고: 1. 다음 용매를 추가하기 전에 액체가 투명한지 확인하십시오.
2. 용매를 순서대로 추가해야 합니다. 다음 용매를 추가하기 전에 이전 추가에서 얻은 용액이 투명한 용액인지 확인해야 합니다. 와동, 초음파 또는 뜨거운 물 중탕과 같은 물리적 방법을 사용하여 용해를 도울 수 있습니다.

작용 메커니즘 (Mechanism of Action)

Targets/IC₅₀/Ki	gamma-secretase (cell-free assay) 6.2 nM
시험관 내(In vitro)	Nirogacestat (PF-03084014) inhibits Notch receptor cleavage in cellular assays using HPB-ALL cells that harbor mutations in both the heterodimerization and PEST domains in Notch1 with IC50 of 13.3 nM. It downregulates Notch target genes Hes-1 and cMyc expression in HPB-ALL cells with IC50 of <1 nM and 10 nM, respectively, and inhibits cell growth of a subset of human T-ALL cell lines (HPB-ALL, DND-41, TALL-1, and Sup-T1) through induction of cell cycle arrest and apoptosis with IC50s of 30–100 nM. This compound reduces proliferation of HUVECs with IC50 of 0.5 μM, and decreases the lumen formation with an IC50 value of 50 nM. It (1 μM) has no antiproliferative effect in MX1 cells; however, it inhibits migration by 95%.
키나아제 분석	γ-secretase assay
키나아제 분석	A DNA fragment encoding amino acids 596 - 695 of the 695-aa isoform of APP (APP695) and the Flag sequence (DYKDDDDK) at the C terminus is generated by PCR amplification with suitably designed oligonucleotides and the APP695 cDNA. The Met that serves as the translation start site is residue 596 of APP695 (the P1 residue with respect to theβ-secretase cleavage site). This DNA fragment is inserted into the prokaryotic expression vector pET2-21b. The recombinant protein, C100Flag, is overproduced in Escherichia coli [strain BL21(DE3)] and purified by Mono-Q column chromatography. C100Flag (1.7 μM) is incubated with cell membranes (0.5 mg/mL) in the presence of CHAPSO, CHAPS (3-[(3-cholamidopropyl)dim-ethylammonio]-1-propanesulfonate), or Triton X-100 (0, 0.125, 0.25, 0.5, or 1%) in buffer B (50 mM Pipes, pH 7.0y 5mM MgCl₂/5 mM CaCl₂/150 mM KCl) at 37°C. The reactions are stopped by adding RIPA (150 mM NaCl/1.0% NP-40/0.5% sodium deoxycholatey 0.1% SDS/50 mM Tris HCl, pH 8.0) and boiling for 5 min. The samples ae centrifuged and the supernatant solutions are assayed for the Aβ peptides by ECL. The Aβ40- and Aβ42-related products from γ-secretase-mediated processing of C100Flag possess a Met at the N terminus and are thus defined as M-Aβ40 and M-Aβ42, respectively. Likewise, supernatant solution (0.125 mg/mL) from CHAPSO-extracted HeLa cell membranes (solubilized γ-secretase) is incubated with C100Flag (1.7 μM) in buffer B containing 0.25% CHAPSO and subsequently assayed for M-Aβ40 and M-Aβ42 by using ECL. This compound, Nirogacestat (PF-03084014), is used in the experimental context.
생체 내(In vivo)	Nirogacestat (PF-03084014) orally administrated in a single dose of 200 mg/kg causes maximal NICD inhibition for ∼80% in xenograft HPB-ALL tumors. It shows robust antitumor activity in this mode with a maximal tumor growth inhibition of ∼92% at a dose of 150 mg/kg, accompanied by a significant reduction of NICD/Notch1, tumor mitotic index (Ki67), and apoptosis (activated caspase-3) staining. At 120 mg/kg, this compound induces apoptosis, antiproliferation, reduces tumor cell self-renewal ability, impairs tumor vasculature, and decreases metastasis activity in breast cancer HCC1599 tumor-bearing mice. Its treatment displays significant antitumor activity in various types of the breast xenograft models with TGI value of at least 50%.
참조	[1] https://pubmed.ncbi.nlm.nih.gov/20530712/ [2] https://pubmed.ncbi.nlm.nih.gov/22806875/ [3] https://pubmed.ncbi.nlm.nih.gov/10801983/

적용 분야 (Applications)

방법	바이오마커	이미지	PMID
Western blot	N1ICD / Hes-1 / Hey-1 / p-MEK / MEK / c-PARP		23402814

임상시험 정보 (Clinical Trial Information)

(데이터 출처 https://clinicaltrials.gov, 업데이트 날짜 2024-05-22)

NCT 번호	모집	조건	스폰서/협력자	시작일	단계
NCT02338531	Withdrawn	Breast Cancer	Jules Bordet Institute	June 2015	Phase 2
NCT02299635	Terminated	Triple Negative Breast Neoplasms	Pfizer	February 3 2015	Phase 2
NCT02109445	Terminated	Metastatic Cancer Pancreas	Pfizer\|Academic GI Cancer Consortium (AGICC)	September 3 2014	Phase 2
NCT01876251	Terminated	Breast Cancer Metastatic	Pfizer	November 4 2013	Phase 1

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

Nirogacestat (PF-03084014) γ-Secretase inhibitor

화학 구조

분자량: 489.64

품질 관리 (Quality Control)

화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

용해도 (Solubility)

몰농도 계산기

생체 내 제형 계산기 (투명한 용액)

작용 메커니즘 (Mechanism of Action)

적용 분야 (Applications)

임상시험 정보 (Clinical Trial Information)