HL156A

HL156A
Clinical data
Other names	IM156, HL271 acetate, UNII-4G3BUV6ZSK
Identifiers
	IUPAC name N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide;
CAS Number	1422365-93-2;
PubChem CID	71512108;
ChemSpider	92169512;
UNII	4G3BUV6ZSK;
CompTox Dashboard (EPA)	DTXSID501336867 ;
Chemical and physical data
Formula	C13H16F3N5O
Molar mass	315.300 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CCN(C1)C(=NC(=NC2=CC=C(C=C2)OC(F)(F)F)N)N;
	InChI InChI=1S/C13H16F3N5O/c14-13(15,16)22-10-5-3-9(4-6-10)19-11(17)20-12(18)21-7-1-2-8-21/h3-6H,1-2,7-8H2,(H4,17,18,19,20); Key:NGFUHJWVBKTNOE-UHFFFAOYSA-N;

HL156A is a derivative of metformin and a potent oxidative phosphorylation inhibitor and AMP-activated protein kinase activating biguanide.^[1]^[2] Certain types of cancer cells requires oxidative phosphorylation to survive. By targeting it, HL156A might help in improving anticancer therapy.^[3] It is more potent than acadesine or metformin at activating AMP-activated protein kinase.^[2] It is synthesized by Hanall Biopharma.^[4]

Medical uses

It is in phase 1 trial in patients with advanced solid tumor and lymphoma.^[5]^[1]

Pharmacology

Apart from AMP-activated protein kinase activation, it also inhibits expression and activation of insulin-like growth factor-1, protein kinase B, mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinases.^[6]^[7]

Research

It is researched in multiple conditions like liver and renal fibrosis,^[2]^[8] cancer^[6]^[9] and drug resistance in cancer.^[7] HL176OUT04, a drug with similar pharmacology, has been also developed.^[10]

References

^ ^a ^b Rha SY, Beom SH, Shin YG, Yim DS, Moon YW, Kim TW, et al. (2020). "Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors". Journal of Clinical Oncology. 38 (15_suppl): 3590. doi:10.1200/JCO.2020.38.15_suppl.3590. ISSN 0732-183X. S2CID 219780562.
^ ^a ^b ^c Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, et al. (2018). "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model". PLOS ONE. 13 (8): e0201692. Bibcode:2018PLoSO..1301692T. doi:10.1371/journal.pone.0201692. PMC 6116936. PMID 30161162.
^ Xu Y, Xue D, Bankhead A, Neamati N (December 2020). "Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?". Journal of Medicinal Chemistry. 63 (23): 14276–14307. doi:10.1021/acs.jmedchem.0c01013. PMC 9298160. PMID 33103432. S2CID 225072329.
^ Ju KD, Kim HJ, Tsogbadrakh B, Lee J, Ryu H, Cho EJ, et al. (March 2016). "HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis". American Journal of Physiology. Renal Physiology. 310 (5): F342–F350. doi:10.1152/ajprenal.00204.2015. PMID 26661649.
^ "A Multi Center, Open-label, Phase 1 Clinical Trial to Evaluate the Safety, Tolerability, and Preliminary Efficacy of IM156 in Patients with Advanced Solid Tumors and Lymphoma". 15 October 2020.
^ ^a ^b Lam TG, Jeong YS, Kim SA, Ahn SG (March 2018). "New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways". Cancer Science. 109 (3): 699–709. doi:10.1111/cas.13482. PMC 5834796. PMID 29285837.
^ ^a ^b Jeong YS, Lam TG, Jeong S, Ahn SG (August 2020). "Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells". Pharmaceuticals. 13 (9): 218. doi:10.3390/ph13090218. PMC 7560051. PMID 32872293.
^ Lee HS, Shin HS, Choi J, Bae SJ, Wee HJ, Son T, et al. (October 2016). "AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages". International Journal of Oncology. 49 (4): 1407–1414. doi:10.3892/ijo.2016.3627. PMID 27498767.
^ Choi J, Lee JH, Koh I, Shim JK, Park J, Jeon JY, et al. (October 2016). "Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A)". Oncotarget. 7 (40): 65643–65659. doi:10.18632/oncotarget.11595. PMC 5323181. PMID 27582539.
^ Hyeonsang S (2016). The AMPK activators, HL156A and HL176OUT04 reduce thioacetamide-induced hepatic fibrosis via the inhibition of hepatic stellate cell activation (Ph.D. thesis). 서울대학교 융합과학기술대학원 (Seoul National University Graduate School of Convergence Science and Technology). hdl:10371/133411.

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[RhaBeom2020-1] Rha SY, Beom SH, Shin YG, Yim DS, Moon YW, Kim TW, et al. (2020). "Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors". Journal of Clinical Oncology. 38 (15_suppl): 3590. doi:10.1200/JCO.2020.38.15_suppl.3590. ISSN 0732-183X. S2CID 219780562.

[pmid30161162-2] Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, et al. (2018). "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model". PLOS ONE. 13 (8): e0201692. Bibcode:2018PLoSO..1301692T. doi:10.1371/journal.pone.0201692. PMC 6116936. PMID 30161162.

[XuXue2020-3] Xu Y, Xue D, Bankhead A, Neamati N (December 2020). "Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?". Journal of Medicinal Chemistry. 63 (23): 14276–14307. doi:10.1021/acs.jmedchem.0c01013. PMC 9298160. PMID 33103432. S2CID 225072329.

[4] Ju KD, Kim HJ, Tsogbadrakh B, Lee J, Ryu H, Cho EJ, et al. (March 2016). "HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis". American Journal of Physiology. Renal Physiology. 310 (5): F342–F350. doi:10.1152/ajprenal.00204.2015. PMID 26661649.

[5] "A Multi Center, Open-label, Phase 1 Clinical Trial to Evaluate the Safety, Tolerability, and Preliminary Efficacy of IM156 in Patients with Advanced Solid Tumors and Lymphoma". 15 October 2020.

[pmid29285837-6] Lam TG, Jeong YS, Kim SA, Ahn SG (March 2018). "New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways". Cancer Science. 109 (3): 699–709. doi:10.1111/cas.13482. PMC 5834796. PMID 29285837.

[pmid32872293-7] Jeong YS, Lam TG, Jeong S, Ahn SG (August 2020). "Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells". Pharmaceuticals. 13 (9): 218. doi:10.3390/ph13090218. PMC 7560051. PMID 32872293.

[pmid27498767-8] Lee HS, Shin HS, Choi J, Bae SJ, Wee HJ, Son T, et al. (October 2016). "AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages". International Journal of Oncology. 49 (4): 1407–1414. doi:10.3892/ijo.2016.3627. PMID 27498767.

[pmid27582539-9] Choi J, Lee JH, Koh I, Shim JK, Park J, Jeon JY, et al. (October 2016). "Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A)". Oncotarget. 7 (40): 65643–65659. doi:10.18632/oncotarget.11595. PMC 5323181. PMID 27582539.

[10] Hyeonsang S (2016). The AMPK activators, HL156A and HL176OUT04 reduce thioacetamide-induced hepatic fibrosis via the inhibition of hepatic stellate cell activation (Ph.D. thesis). 서울대학교 융합과학기술대학원 (Seoul National University Graduate School of Convergence Science and Technology). hdl:10371/133411.

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HL156A

Medical uses

Pharmacology

Research

See also

References