Indenos and Azas Overview

Cushman M. Design and Synthesis of Indenoisoquinoline Topoisomerase I Inhibitors for Cancer Chemotherapy. J. Med. Chem. 2021, 64, 24, 17572–17600.

Pommier Y, Cushman M. The indenoisoquinoline non-Camptothecin topoisomerase I inhibitors: update and perspectives. Mol Cancer Ther. 2009 May;8(5):1008-14. Epub 2009 Apr 21.

C-MYC Promoter G-Quadruplex Regulation

Bacolla A, Z Ye, Z Ahmed, J Tainer. Cancer mutational burden is shaped by G4 DNA, replication stress, and mitochondrial dysfunction. Prog Biophys Mol Biol. DOI: 10.1016/jbiomolbio.2019.03.004-0079-6107

Hui WWI, A Simeone, KG Zyner et al. Single-cell mapping of DNAG-quadruplex structures in human cancer cells. Nature (2021) 11:23641.

Kim N. The Interplay between G-quadruplex and Transcription. Cur Medicinal Chem 2019,26,2898-2917. DOI: 10.2174/0929867325666171229132619.

Kosiol N, S Juranek, P Brossart erttr al. G-quadruplexes: a promising target for cancer therapy. Mol Cancer (2021) 20-40. DOI: 10.1186/s12943-021-01328-4.

Neidle S, A Ahmed, R Angell, S Oxenford. The potent quadruplex-binding compound QN-302 shows anti-tumor activity in patient-derived in vivo models of pancreatic cancer. AACR Abstract 4069. April 2022. (Qualigen)

Paul R, T Das, M Debnath, et al. G-Quadruplex-Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c-MYC and BCL2 Expression. ChemBioChem 2019,20,1-9. Doi: 10.1002/cbic.201900534.

Psaras AM, S Valiuska, V Noe et al. Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides. Can Res Abstract 675 (2022)82 (12_Supplement);675.

Siddiqui-Jain, CL Grand, DJ Bearss et al. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. PNAS (2002) 99(18) 11593-11598. DOI: 10.1073/pnas.182256799

Kiselev E, K Agama, Y Pommier, MCushman. Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents: A Systematic Study of Structure-Acftivity Relationships. J Med Chem 2012,55,1682-1697.

Thomas A and Y Pommier. Targeting Topoisomerase I in the Era of Precision Medicine. Clin Cancer Res. 2019,15:25(22):6581-6589. Doi://10.1158/1078-0432,CC%-19—1089.

7-Azas and Indenos in G-quadruplex C-Myc Inhibition

Beck DE, PVN Reddy, Y Pommier, M Cushman et al. Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline TopisomerSE I Poisons. J Med Chem 2016, 59,8,3840-3853.

Berroyer A, A Bacolla, J Tainer, N Kim. Cleavage-defective Topoisomerase I mutants sharply increase G-quadruplex-associated genomic instability. Microb Cell 2022; 9(3):52-68. DOI: 10.15698/mic2022.03.771.

Cushman M, D Nagarathnam, D Gopal, H M He, C M Lin, E Hamel. Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents. J Med Chem 1992,35,12,2293-2306.

Elsayed SA, Y Su, P Wang, MY Pommier, M Cushman et al. Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents that Inhibit Topoisomerase 1. J Med Chem 2017,60,13,5364-5376.

Kiselev E, T Dexheimer, Y Pommier, M Cushman. Design, Synthesis, and Evaluation of Dibenzo(c,h) (1,6) napthyridines as Topoisomerase I Inhibitors ND Potential Anticancer Agents. J Med Chem 2010,53,24,8716-8726.

Kiselev, S Deguire, Y Pommier, M Cushman et al. 7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents. J Med Chem 2011, 54:6106-6116. Doi: 10.1021/jm200719v.

Kiselev E, D Sooryakumar, K Agama, M Cushman, Y Pommier. Optimization of the Lactam Side Chair of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells. J Med Chem 2014; 57:1289-1298. Doi: 10.1021/jm40147v1.

Liu W, C Lin, D Yang et al. Structures of 1:1 and 2:1 complexes of BMVC and MYC promoter G-quadruplex reveal a mechanism of ligand conformation adjustment for G4-recognition.

Wang P, MSA Elsayed, Y Pommier, M Cushman et al. Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdpd1), and Tyrosyl-DNA Phosphodiesterase 2 (tdp2). J Med Chem 2017, 60,8,3275-3288.

Wang KB, D Yang, M Cushman, et al. Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J Am. Chem. Soc. 2019, 141, 28, 11059-11070. DOI: 10.1021/jacs.9b02679

Indenos work when Irinotecan Resistance

Candeil L,I Gourdier, D Peyron …Y Pommier et al. ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan‐treated metastases. International Journal of Cancer 2004;109: 848-854. DOI:

Jandu H, K Aluzaite, L Fogh, et al. Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines.
BMC Cancer (2016) 16:34.
DOI 10.1186/s 12885-016-2071-1

Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygård SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rømer MU, Brünner N, Moreira JM. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol. 2015 Jun;9(6):1169-85. doi: 10.1016/j.molonc.2015.02.008. Epub 2015 Feb 24. PMID: 25759163

Veterinary Clinical Trials

Burton JH, C Mazcko, A LeBlanc, J H Doroshow, Y Pommier et al. NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors In Naturally Occurring Canine Lymphoma. Clin Cancer Res;24(13);5830-40,2018.
Eiseman JL, Holleran J, McCormick D, et al… Plasma and Tumor pharmacokinetics of IV LMP 744, a novel Indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. Abstract # 4632 Presented at the AACR Annual Meeting 2015, Philadelphia, PA
Muzzio M, JH Beumer, J Holleran et al. Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs. Cancer Chemother Pharmacol. 2015 May; 75(5): 1015–1023.  doi: 10.1007/s00280-015-2722-y

Clinical Studies

Doroshow, J.H., J.J. Ji, A. Chen, et al. (2012). Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors. J Clin Oncol. 30s:A3031.
Fox, B.M., Xiao, X. Antony, S., et al. (2003). Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. J Med Chem. 46:3275-3282.

Schlafen 11 (SLFN11) Biomarkers

Ballestrero A, D Bedognetti, D Ferraioli..Pommier et al. Report of the first SLFN11 monothematic workshop: from function to role as a biomarker in cancer. J Trans Med 2017; 15:199-198. DoI 10.1186/s12967-017-1296-3.
Buettner R. Awakening of SCHLAFEN11 by immunohistochemistry: a new biomarker predicting response to chemotherapy. Virchows Archiv 2021.
Coussy F, R El-Botty…Y Pommier et al. BRCAness, SLFN11, and RBI loss predict response to topoisomerase 1 inhibitors in triple negative breast cancers. Sci.Transl. Med. 2020;12(531).pii: eaax2625. doi: 10.1126/scitranslmed.aax2625

Murai J and Y Pommier. Abstract 5875: Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents. AACR 2017. DOI: 10.1158/1538-7445.AM2017-5975.

Murai J, SW Tang, E Leo…Y Pommier . SLFN11 Blocks Stress Replication Forks Independently of ATR. J Mol Cell 2018; 69(3):371-384.

Pommier Y, L Marzi, ZW Ohler..M Cushman et al. Abstract 4855: Indotecan (LMP400), Imidotecan (LMP776) and LMP744: a new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression. 2018 Proceedings AACR . DOI: 10.1158-7445.AM2018-4855.

Glioblastoma and Pontine Gliomas

Cenci T, M Martini, N Montano et al. Prognostic Releance of c-Muc and BMI1 Expression in Patients with Glioblatoma. Amer J Clin Pathology,2012, 138 (3), 390-396. Htpps://

Fatma H, S Maurya, H Siddique. Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance. Sem in Cancer Biol (2022) 83,166-176.

Kool M, J Koster,J Bunt et al. Integrated Genomics Identifi3e Five Medulloblatoma Subtypes with Distinct Genetic PROFILES, Pathway Signatures and Clinicopathological Features. PloSONE 3(8):e3088.
Kool M, A Korshunov, M Remke et al. Molecular subgroups of medulloblaoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT,SHH,Group 3, and Group 4 medulloblastomas. Acta Neuropathol (2012) 123:473-484. Doi: 10.1007/s00401-012-0958-8
Xie Y,T Bergstrom, Y Jiang et al. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes. EBioMedicine 2(2015) 1351-1363