Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant

References

• Siegel RL, Miller Kimberly D, Fuchs Hannah E, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
   PubMed Web of Science ®Google Scholar
• Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D. The chronic myelogenous leukemia specific P210-Protein is the product of the Bcr/Abl hybrid gene. Science. 1986;233(4760):212–214.
   PubMed Web of Science ®Google Scholar
• Faderl S, Garcia‐Manero G, Thomas DA, Kantarjian HM. Philadelphia chromosome‐positive acute lymphoblastic leukemia–current concepts and future perspectives. Rev Clin Exp Hematol. 2002;6(2):142–160.
   PubMedGoogle Scholar
• Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002;1(7):493–502.
   PubMed Web of Science ®Google Scholar
• Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MWN, Silver RT, Goldman JM, Stone RM, IRIS Investigators, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–2417.
   PubMed Web of Science ®Google Scholar
• Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–927.
   PubMed Web of Science ®Google Scholar
• Pandrala M, Bruyneel AAN, Hnatiuk AP, Mercola M, Malhotra SV. Designing novel BCR-ABL inhibitors for chronic myeloid leukemia with improved cardiac safety. J Med Chem. 2022;65(16):10898–10919.
   PubMedGoogle Scholar
• Le Coutre P, Ottmann OG, Giles F, Kim D-W, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O'Brien SG, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834–1839.
   PubMed Web of Science ®Google Scholar
• Santos FPS, Kantarjian H, Cortes J. Quintas-Cardama A. Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Curr Opin Invest Dr. 2010;11(12):1450–1465.
   PubMedGoogle Scholar
• Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LAM, Das J, Doweyko AM, et al. Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658–6661.
   PubMed Web of Science ®Google Scholar
• Puttini M, Coluccia AML, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl(+) neoplastic cells. Cancer Res. 2006;66(23):11314–11322.
   PubMed Web of Science ®Google Scholar
• Roychowdhury S, Talpaz M. Managing resistance in chronic myeloid leukemia. Blood Rev. 2011;25(6):279–290.
   PubMed Web of Science ®Google Scholar
• Quintas-Cardama A, Cortes J. Therapeutic options against BCR-ABL1 T315I-positive chronic myelogenous leukemia. Clin Cancer Res. 2008;14(14):4392–4399.
   PubMed Web of Science ®Google Scholar
• Zhang D, Li P, Gao Y, Song Y, Zhu Y, Su H, Yang B, Li L, Li G, Gong N, et al. Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia. J Med Chem. 2021;64(11):7434–7452.
   PubMed Web of Science ®Google Scholar
• Huang W-S, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, et al. Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant. J Med Chem. 2010;53(12):4701–4719.
   PubMed Web of Science ®Google Scholar
• O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang W-S, Xu Q, et al. AP24534, a Pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–412.
   PubMed Web of Science ®Google Scholar
• Yeung DT, Shanmuganathan N, Hughes TP. Asciminib: a new therapeutic option in chronic-phase CML with treatment failure. Blood. 2022;139(24):3474–3479.
   PubMed Web of Science ®Google Scholar
• Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, Dodd S, Drueckes P, Fabbro D, Gabriel T, et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J Med Chem. 2018;61(18):8120–8135.
   PubMed Web of Science ®Google Scholar
• Cortes JE, Hughes TP, Mauro MJ, Hochhaus A, Rea D, Goh YT, Janssen J, Steegmann JL, Heinrich MC, Talpaz M, et al. Asciminib, a First-in-Class STAMP inhibitor, provides durable molecular response in Patients (pts) with Chronic Myeloid Leukemia (CML) Harboring the T315I mutation: primary efficacy and safety results from a phase 1 trial. Blood. 2020;136(Supplement 1):47–50.
   Google Scholar
• Ren X, Pan X, Zhang Z, Wang D, Lu X, Li Y, Wen D, Long H, Luo J, Feng Y, et al. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated Breakpoint Cluster Region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013;56(3):879–894.
   PubMed Web of Science ®Google Scholar
• Jiang Q, Li Z, Qin Y, Li W, Xu N, Liu B, Zhang Y, Meng L, Zhu H, Du X, et al. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2022;15(1):113.
   PubMed Web of Science ®Google Scholar
• Ivanova ES, Tatarskiy VV, Yastrebova MA, Khamidullina AI, Shunaev AV, Kalinina AA, Zeifman AA, Novikov FN, Dutikova YV, Chilov GG, et al. PF-114, a novel selective inhibitor of BCR-ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int J Oncol. 2019;55(1):289–297.
   PubMed Web of Science ®Google Scholar
• Mian AA, Rafiei A, Haberbosch I, Zeifman A, Titov I, Stroylov V, Metodieva A, Stroganov O, Novikov F, Brill B, et al. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph plus) leukemias harboring the T315I mutation. Leukemia. 2015;29(5):1104–1114.
   PubMed Web of Science ®Google Scholar
• Desai B, Dixon K, Farrant E, Feng Q, Gibson KR, van Hoorn WP, Mills J, Morgan T, Parry DM, Ramjee MK, et al. Rapid discovery of a novel series of Abl Kinase inhibitors by application of an integrated microfluidic synthesis and screening platform. J Med Chem. 2013;56(7):3033–3047.
   PubMed Web of Science ®Google Scholar
• El-Damasy AK, Cho NC, Nam G, Pae AN, Keum G. Discovery of a nanomolar multikinase inhibitor (KST016366): a new benzothiazole derivative with remarkable broad-spectrum antiproliferative activity. Chemmedchem. 2016;11(15):1587–1595.
   PubMed Web of Science ®Google Scholar
• El-Damasy AK, Jin H, Seo SH, Bang EK, Keum G. Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity. Eur J Med Chem. 2020;207:112710
   PubMed Web of Science ®Google Scholar
• El-Damasy AK, Cho NC, Kang SB, Pae AN, Keum G. ABL kinase inhibitory and antiproliferative activity of novel picolinamide based benzothiazoles. Bioorg Med Chem Lett. 2015;25(10):2162–2168.
   PubMed Web of Science ®Google Scholar
• El-Damasy AK, Jin HW, Park JW, Kim HJ, Khojah H, Seo SH, et al. Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and broad-spectrum anticancer activity. J Enzym Inhib Med Ch. 2023;38(1):2189097.
   PubMed Web of Science ®Google Scholar
• Dai Y, Hartandi K, Ji Z, Ahmed AA, Albert DH, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KB, et al. Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem. 2007;50(7):1584–1597.
   PubMed Web of Science ®Google Scholar
• Tan FH, Putoczki TL, Stylli SS, Luwor RB. Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies. Onco Targets Ther. 2019;12:635–645.
   PubMed Web of Science ®Google Scholar
• Kuchukulla RR, Hwang I, Park SW, Moon S, Kim SH, Kim S, Chung HW, Ji M-J, Park H-M, Kong G, et al. Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers. Pharmaceuticals-Base. 2022;15(9):1041.
   PubMed Web of Science ®Google Scholar
• Teo YL, Ho HK, Chan A. Metabolism-related pharmacokinetic drug-drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations. Br J Clin Pharmacol. 2015;79(2):241–253.
   PubMed Web of Science ®Google Scholar
• Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015;58(9):4066–4072.
   PubMed Web of Science ®Google Scholar
• Zhou T, Commodore L, Huang W-S, Wang Y, Thomas M, Keats J, Xu Q, Rivera VM, Shakespeare WC, Clackson T, et al. Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance. Chem Biol Drug Des. 2011;77(1):1–11.
   PubMed Web of Science ®Google Scholar