HL156A explained

Cas Number:1422365-93-2
Pubchem:71512108
Chemspiderid:92169512
Unii:4G3BUV6ZSK
Synonyms:IM156, HL271 acetate, UNII-4G3BUV6ZSK
Iupac Name:N'-[N'-[4-(trifluoromethoxy)phenyl]carbamimidoyl]pyrrolidine-1-carboximidamide
C:13
H:16
F:3
O:1
N:5
Smiles:C1CCN(C1)C(=NC(=NC2=CC=C(C=C2)OC(F)(F)F)N)N
Stdinchi: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)
Stdinchikey:NGFUHJWVBKTNOE-UHFFFAOYSA-N

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

Medical uses

It is in phase 1 trial in patients with advanced solid tumor and lymphoma.[4] [5]

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.

Research

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

See also

Notes and References

  1. Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, Lee H, Yu KS, Oh YK, Kim HJ, Ahn C, Oh KH . 6 . 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 . 2018 . 30161162 . 6116936 . 10.1371/journal.pone.0201692 . free . 2018PLoSO..1301692T .
  2. Xu Y, Xue D, Bankhead A, Neamati N . Why All the Fuss about Oxidative Phosphorylation (OXPHOS)? . Journal of Medicinal Chemistry . 63 . 23 . 14276–14307 . December 2020 . 33103432 . 9298160 . 10.1021/acs.jmedchem.0c01013 . 225072329 .
  3. Ju KD, Kim HJ, Tsogbadrakh B, Lee J, Ryu H, Cho EJ, Hwang YH, Kim K, Yang J, Ahn C, Oh KH . 6 . 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 . March 2016 . 26661649 . 10.1152/ajprenal.00204.2015 . free .
  4. Web site: 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.
  5. Rha SY, Beom SH, Shin YG, Yim DS, Moon YW, Kim TW, Kim SY, Kim GM, Kim HS, Cheong JH, Lee YW . 6 . 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. 2020. 3590. 0732-183X. 10.1200/JCO.2020.38.15_suppl.3590. 219780562.
  6. Lee HS, Shin HS, Choi J, Bae SJ, Wee HJ, Son T, Seo JH, Park JH, Kim SW, Kim KW . 6 . 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 . October 2016 . 27498767 . 10.3892/ijo.2016.3627 . free .
  7. Lam TG, Jeong YS, Kim SA, Ahn SG . 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 . March 2018 . 29285837 . 5834796 . 10.1111/cas.13482 .
  8. Choi J, Lee JH, Koh I, Shim JK, Park J, Jeon JY, Yun M, Kim SH, Yook JI, Kim EH, Chang JH, Kim SH, Huh YM, Lee SJ, Pollak M, Kim P, Kang SG, Cheong JH . 6 . Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A) . Oncotarget . 7 . 40 . 65643–65659 . October 2016 . 27582539 . 5323181 . 10.18632/oncotarget.11595 .
  9. Jeong YS, Lam TG, Jeong S, Ahn SG . Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells . Pharmaceuticals . 13 . 9 . 218 . August 2020 . 32872293 . 7560051 . 10.3390/ph13090218 . free .
  10. Hyeonsang S . Ph.D. . The AMPK activators, HL156A and HL176OUT04 reduce thioacetamide-induced hepatic fibrosis via the inhibition of hepatic stellate cell activation. 2016. 서울대학교 융합과학기술대학원 (Seoul National University Graduate School of Convergence Science and Technology) . 10371/133411. Thesis.

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