(Melatonin) HIF-1 전사 인자를 표적으로 하는 항암제의 최근 개발 개요

2021

https://www.mdpi.com/2072-6694/13/11/2813/htm

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

**Melatonin

 

 

그림 1. HIF-1 및 HIF-1 억제제를 표적으로 하는 억제제 활성화 이면의 표준 조절 메커니즘.

 

HIF-1 활성은 주로 PHD 의존성 수산화 및 VHL 매개 유비퀴틴화를 통해 HIF-1α 단백질 안정성 수준에서 조절됩니다

그림 2. HIF-1 활성화 이면의 비표준 규제 메커니즘. 

 

HIF-1 활성은 HIF-1α 유전자의 전사 개시, HIF-1α mRNA의 번역 개시, HIF-1α 단백질의 안정성 및 HIF-1α의 전사 활성화를 포함하는 여러 단계에서 조절됩니다. 

 

Table 1. Potential HIF-1 inhibitors under development.

HIF-1 Inhibitors        Target Molecules                                      Tumors/Cell Lines

Transcriptional initiation
Flavopiridol	blocking phosphorylation of RNA polymerase II’s COOH-terminal domain	acute myeloid leukemia, advanced renal cell carcinoma
Aminoflavone	AhR	breast cancer cells (MCF7), human renal cell lines
mRNA stabilization
EZN-2968	HIF-1α mRNA	prostate (15PC3, PC3, and DU145), glioblastoma (U373) cells, duodenal neuroendocrine tumor
Translational initiation
Rapamycin	mTOR	prostate cancer cells (PC-3)
Cetuximab	EGFR	HNSCC cells (FaDu, HN5, UMSCC1, and OSC19)
Buparlisib	PI3K	breast cancer
KC7F2	mTOR, S6K, 4EBP1	U251MG, MCF7, PC3, LNZ308, LN229 cells
2-MEs	tubulin	MCF7, MDA-MB-231, PC-3, ovarian cancer, multiple myeloma
Digoxin	Na+/K+ ATPase	Hep3B, 293, 293T, PC3, P493
AZD6738, VX-970	ATR	esophageal cancer cells (OE21, FLO-1) (VX-970)
Protein stabilization
Melatonin, NB-5-MT	GSK-3β, activating PHDs	colon cancer cells (HCT116), prostate cancer cells (DU145, PC-3, LNCaP), breast cancer cells (MCF-7, MDA-MB-231), renal cell carcinoma (RenCa)
LW6	inducing pVHL expression	HCT116
GYY4137	slow-releasing H2S donor	HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11, U2OS
Ganetespib	ATP-binding site of HSP90	NSCLC (NCI-H1975, HCC827) cells, colorectal cancer (HCT116, HT29), non-small cell lung cancer
Apigenin	CK2 activity	multiple myeloma cells, pancreatic cancer cells (S2-013, CD18)
Lonafarnib	interaction between HSP90 and HIF-1α	non-small cell lung carcinoma, breast cancer
Vorinostat	increasing acetylation of HSP90	Hep3B, HepG2, U2OS, MG63, U87 MG, HuH7
Romidepsin (FK228)	HDAC	Lewis lung carcinoma (LLC), HT1080
Trichostatin	HDAC	tongue squamous cell carcinoma SCC-6, BAECs, 786-0 (VHL-negative), HEK 293 cells, Lewis lung carcinoma cells, HepG2
Heterodimerization
Acriflavine	PAS-B domain of HIF-1α	HEK293, HeLa, Hep3B-c1, PC-3, P493
DNA binding
Echinomycin	binding to HRE sequences	U251, MCF-7, non-small cell lung carcinoma, soft tissue sarcoma
Anthracycline	HIF-HRE binding	HK-2. HeLa, A498, KMRC-3 VHL-defective renal cell carcinoma (RCC) cells, Caki-1 VHL-competent renal cell carcinoma cells
Radicicol	HIF-DNA binding, HSP90	SKBR3, Hep 3B
Transactivation
Bortezomib	PI3K/Akt/mTOR, MAPK, p300 recruitment	prostate cancer cells, Hep3B, HEK293, ARH77, U299 cells, RCC, breast cancer, rectal carcinoma, nasopharyngeal, neuroendocrine carcinoma, prostate cancer
Other steps
PX-478	inhibiting HIF-1α deubiquitination, reducing HIF-1α mRNA and HIF-1α translation	PC-3, MCF-7, HT-29, Panc-1, BxPC-3 cells, RCC4, RCC4/VHL, HCT116
Camptothecin analogues (TPT, EZN-2208)	topoisomerase-1	HEK293, U251, leukemia cell lines, neuroblastoma cells (GI-LI-N, LAN-5) derived from metastatic
CRLX101	topoisomerase-1	ovarian cancer, breast cancer, renal cell carcinoma
Metformin	Mitochondria complex I, XBP1	HCT116, HCC, NSCLC, etc.

AF, aminoflavone; AhR, aryl hydrocarbon receptor; ATR, ataxia telangiectasia and Rad3-related kinase; CK2, casein kinase 2; EGFR, epidermal growth factor receptor; HDACs, histone deacetylases; HIF-1, hypoxia-inducible factor 1; HNSCC, head and neck squamous cell carcinoma; HRE, hypoxia response element; H2S, hydrogen sulfide; HSP90, heat shock protein 90; GSK-3β, glycogen synthase kinase-3β; MAPK, mitogen-activated protein kinase; 2-ME, 2-methoxyestradiol; RCC, renal cell carcinoma; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; PAS, Per-Arnt-Sim; PI3K, phosphatidylinositol-3-kinase; pVHL, von Hippel-Lindau protein; TPT, topotecan; TSA, trichostatin A; XBP1, X-box binding protein 1.

Table 2. Potential HIF-1 inhibitors under development.

HIF-1 Inhibitors              Animal Models                                       Clinical Trials                                         References

Transcriptional initiation
Flavopiridol	No animal model looking at effect on hypoxia/HIF-1	Not in clinical use	[35,36,37,38,39]
Aminoflavone (AF)	MCF-7 xenografts	Phase 1 (Completed)	[40,41,42,43]
mRNA stabilization
EZN-2968	DU145 xenograft	Phase 1 (Completed)	[44,45]
Translational initiation
Rapamycin	LKB1 ± mice (Peutz-Jeghers syndrome model), ACHN xenograft, SN12C xenograft	FDA-approved for treatment for renal cell carcinoma (RCC)	[46,47,48]
Cetuximab	Tgfb1/Pten deletion 2cKO mice, CAL27 xenograft	FDA-approved for head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC)	[49,50]
Buparlisib	No animal model looking at effect on hypoxia/HIF-1	Phase 3 (Completed, Terminated)	[51]
KC7F2	No animal model looking at effect on hypoxia/HIF-1	Not in clinical use	[52]
2-MEs	LLC xenograft/MDA-MB-231 xenograft	Phase 2 (Completed)	[53,54,55,56,57]
Digoxin	P493 xenograft/PC3 xenograft	Phase 2 (Completed, Terminated)	[58,59]
AZD6738, VX-970	OE21 xenograft (VX-970)	AZD6738: Phase 2 (In progress)	[60]
		VX-970: Phase 2 (In progress)
Protein stabilization
Melatonin, NB-5-MT	Tumor xenograft models with breast, kidney, prostate, and colon cancer cells in mouse and zebrafish	Not in clinical use	[61,62,63,64,65,66]
LW6	HCT116 xenograft	Not in clinical use	[67]
GYY4137	No animal model looking at effect on hypoxia/HIF-1	Not in clinical use	[68,69]
Ganetespib	Orthotopic implantation of MDA-MB-231, MDA-MB-435	Phase 2 (Completed) Phase 3 (Terminated)	[70,71,72,73]
Apigenin	PC-3 and OVCAR3 Matrigel plug assay	Phase 2 (Terminated)	[74,75,76,77,78]
Lonafarnib	Orthotopic implantation of UMSCC38	Phase 2 (Completed) Phase 3 (Terminated)	[79,80,81,82,83]
Vorinostat	Hep3B xenograft	FDA-approved for cutaneous T-cell lymphoma Phase 2 with results for other cancer types	[84,85,86]
Romidepsin (FK228)	Orthotopic implantation of LLC	FDA-approved for cutaneous T-cell lymphoma Phase 2 with results for other cancer types	[87]
Trichostatin	No animal model looking at effect on hypoxia/HIF-1	Phase 1 (In progress)	[88,89,90]
Heterodimerization
Acriflavine	PC-3 xenografts	Not in clinical use	[91,92,93]
DNA binding
Echinomycin	MDA-MB-231 and SUM-159 xenografts	Phase 2 (Completed)	[94,95,96,97,98]
Anthracycline	HeLa xenografts	Phase 2 (Completed)	[99]
Radicicol	No animal model looking at effect on hypoxia/HIF-1	Not in clinical use	[100,101]
Transactivation
Bortezomib	SiHa xenografts	Phase 1 (Completed)	[102,103,104,105,106]
Other steps
PX-478	HT-29 xenografts	Phase 1 (Completed)	[107,108]
Camptothecin analogues (TPT, EZN-2208)	U251 glioma xenografts	TPT: Phase 1 (Completed)	[109,110,111,112,113]
		EZN-2208 combination with other drugs: Phase 1 (Completed)
CRLX101	orthotopic primary triple-negative breast cancer xenografts	Phase 2 (Completed)	[114,115,116,117]
Metformin	Various types of tumors, e.g., CRC and HCC	Phase 3 (Completed)	[118,119,120,121]

CTCL, cutaneous T-cell lymphoma.