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Evofosfamide (TH-302)

제품 번호: S2757

Evofosfamide (TH-302) is a selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM. It demonstrates 270-fold enhanced cytotoxicity under hypoxia versus their potency under aerobic conditions, and is stable to cytochrome P450 metabolism.
Evofosfamide (TH-302) Chemical Structure

화학 구조

분자량: 449.04

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품질 관리 (Quality Control)

배치: 순도: 99.82%
99.82

세포 배양, 처리 및 작업 농도
(Cell Culture, Treatment & Working Concentration)

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
H460 Cytotoxicity assay 2 hrs Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by Alamar blue staining assay, IC50=0.019μM. 18257544
H460 Cytotoxicity assay 2 hrs Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.1μM. 18257544
HT29 Cytotoxicity assay 2 hrs Cytotoxicity against human HT29 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.2μM. 18257544
H460 Cytotoxicity assay 2 hrs Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by Alamar blue staining assay, IC50=5.1μM. 18257544
H460 Cytotoxicity assay 2 hrs Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=30μM. 18257544
HT29 Cytotoxicity assay 2 hrs Cytotoxicity against human HT29 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=40μM. 18257544
NCI-H460 Cytotoxicity assay 24 hrs Cytotoxicity against human NCI-H460 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=9.08μM. 28350997
HT-29 Cytotoxicity assay 24 hrs Cytotoxicity against human HT-29 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=49.51μM. 28350997
NCI-H460 Cytotoxicity assay 24 hrs Cytotoxicity against human NCI-H460 cells after 24 hrs under hypoxic condition by luminescence-based Cell-Titer Glo assay, IC50=0.0093μM. 29079474
NCI-H460 Cytotoxicity assay 24 hrs Cytotoxicity against human NCI-H460 cells after 24 hrs under normoxic condition by luminescence-based Cell-Titer Glo assay, IC50=6.65μM. 29079474
DU145 Cytotoxicity assay 2 hrs Cytotoxicity against human DU145 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=4.14μM. 29259746
PC3 Cytotoxicity assay 2 hrs Cytotoxicity against human PC3 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=6.49μM. 29259746
HEMC-SS Antiproliferative assay 24 hrs Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under hypoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=0.13μM. 30199705
HEMC-SS Antiproliferative assay 24 hrs Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under normoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=2.9μM. 30199705
NCI-H460 Antiproliferative assay Antiproliferative activity against human NCI-H460 cells in presence of N2, IC50=2μM. 30295477
NCI-H460 Antiproliferative assay Antiproliferative activity against human NCI-H460 cells in presence of O2, IC50=25μM. 30295477
MDA-MB-468 Cytotoxicity assay 4 hrs Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.0062μM. 30885680
SW620 Cytotoxicity assay 4 hrs Cytotoxicity against human SW620 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.052μM. 30885680
MDA-MB-468 Cytotoxicity assay 4 hrs Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=4.403μM. 30885680
SW620 Cytotoxicity assay 4 hrs Cytotoxicity against human SW620 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=20.6μM. 30885680
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 449.04 화학식

C9H16Br2N5O4P

 보관 (수령일로부터)
CAS 번호 918633-87-1 SDF 다운로드 원액 보관

용해도 (Solubility)

In vitro
배치:

DMSO : 90 mg/mL (200.42 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 90 mg/mL

Water : 10 mg/mL

몰농도 계산기

질량 농도 부피 분자량
희석 계산기 분자량 계산기

In vivo
배치:

생체 내 제형 계산기 (투명한 용액)

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

mg/kg g μL

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)

시험관 내(In vitro)

Evofosfamide (TH-302) is selectively potent under hypoxia and stable to liver microsomes. Substitution of the chlorine with bromine on the phosphorus mustard in 3b increases the potency by 10-fold and maintaines the high hypoxic selectivity [Hypoxia cytotoxicity ratio (HCR) = 270]. In both human lung cancer H460 cells and human colon cancer HT29 cells, potent cytotoxicity of this compound is observed under N2. It inhibits H460 cells and HT29 cells with IC90 of 0.1 μM and 0.2 μM, respectively. It shows much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. This compound exhibits potent cytotoxicity to MM cells with hypoxic selectivity and dose dependency. It can induce G0/G1 cell-cycle arrest under hypoxic conditions. The effect of it on cell-cycle machinery is mediated by down-regulating cyclin D1/2/3, CDK4/6, p21cip-1, p27kip-1, and pRb expression, whereas CDK2 expression remained undisturbed. It can induce dose-dependent apoptosis in both human and murine MM cells in hypoxic conditions. TH-302-activated apoptosis is mediated through down-regulating the antiapoptotic proteins BCL-2 and BCL-xL, as well as up-regulating the expression of cleaved proapoptotic protein caspase-3, -8, and -9 and poly ADP-ribose polymerase. In contrast to the hypoxia-specific toxicity, it shows very low toxicity in normoxic condition, even at high concentrations.

생체 내(In vivo)

Evofosfamide (TH-302) inhibits primary tumor growth by 41% on day 25 after implantation, whereas this compound plus a nucleoside analog inhibits primary tumor growth by 96% on day 25. When administered at 6.25, 12.5, 25, or 50 mg/kg in the H460 NSCLC xenograft model QD × 5/wk × 2 wks (once a day for 5 days per week for 2 weeks) i.p., it shows tumor growth inhibition at Day 22 of 43%, 51%, 75%, and 89%, respectively. At 100 mg/kg, it causes a decrease in blood cell counts 3 days after treatment end, but these are totally recovered 7 days post-treatment. Under all tested regimens, it exhibits efficacy metrics ranging from 58% to 89% tumor growth inhibition. Its induced cell killing is breathing oxygen concentration dependent, with the greatest cytotoxicity occurring when the tumor-bearing mice are exposed to low oxygen concentrations. Tumor growth is significantly reduced by this compound in animals breathing 10% O2 compared with 95% O2 breathing. After treatment, the pimonidazole-positive area is significantly decreased at 48 hours after dosing (6.3 % in vehicle vs. 1.8 % in the TH-302 treatment group).

참조
  • [4] https://pubmed.ncbi.nlm.nih.gov/22184053/

임상시험 정보 (Clinical Trial Information)

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

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
NCT02020226 Unknown status
Solid Tumors
Threshold Pharmaceuticals
 November 2013 Phase 1
NCT01833546 Completed
Solid Tumor|Pancreatic Cancer
Merck KGaA Darmstadt Germany|Threshold Pharmaceuticals
 April 18 2013 Phase 1