ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthetic Route to Compounds 11
ACKNOWLEDGMENTS
■
́
The authors thank Flavia Adler, Celine Be, Alexandra Buhles,
Patrick Graff, Aude Izaac, Julia Klopp, Elke Koch, Corinne
Marx, Kerstin Pollehn, Paul Westwood, and Aurelie Winter-
halter for excellent technical assistance, and Anton Kessler,
Martin Klumpp and Kim Twesten for HTS assay.
REFERENCES
■
(1) Slany, R. K. The molecular biology of mixed lineage leukemia.
Haematologica 2009, 94, 984−993.
(2) Muntean, A. G.; Hess, J. L. The pathogenesis of mixed-lineage
leukemia. Annu. Rev. Pathol.: Mech. Dis. 2012, 7, 283−301.
(3) Deshpande, A. J.; Bradner, J.; Armstrong, S. A. Chromatin
modifications as therapeutic targets in MLL-rearranged leukemia.
Trends Immunol. 2012, 33, 563−570.
(4) Krivtsov, A. V.; Hoshii, T.; Armstrong, S. A. Mixed-Lineage
Leukemia Fusions and Chromatin in Leukemia. Cold Spring Harbor
Perspect. Med. 2017, 7, a026658
(5) Wood, K.; Tellier, M.; Murphy, S. DOT1L and H3K79
Methylation in Transcription and Genomic Stability. Biomolecules
2018, 8, 11
(6) Krivtsov, A. V.; Feng, Z.; Lemieux, M. E.; Faber, J.; Vempati, S.;
Sinha, A. U.; Xia, X.; Jesneck, J.; Bracken, A. P.; Silverman, L. B.;
Kutok, J. L.; Kung, A. L.; Armstrong, S. A. H3K79 methylation
profiles define murine and human MLL-AF4 leukemias. Cancer Cell
2008, 14, 355−368.
(7) Bernt, K. M.; Zhu, N.; Sinha, A. U.; Vempati, S.; Faber, J.;
Krivtsov, A. V.; Feng, Z.; Punt, N.; Daigle, A.; Bullinger, L.; Pollock,
R. M.; Richon, V. M.; Kung, A. L.; Armstrong, S. A. MLL-rearranged
leukemia is dependent on aberrant H3K79 methylation by DOT1L.
Cancer Cell 2011, 20, 66−78.
a
Reagents and conditions: (a) (R)-2-methylpropane-2-sulfinamide,
Ti(OEt)4, THF, 45 °C, 2 h, yield 92%; (b) (i) 2-bromo-3-
chloropyridine, iPrMgBr, THF, −55 °C to rt, 2 h; (ii) to 12, −50
°C to rt, toluene, 1 h, yield 71%; (c) 2 M HCl, MeOH/dioxane, rt, 1
h, yield 85%; (d) 4-fluoro-3-nitrobenzenesulfonamide, DMA, 50 °C, 6
h, yield 97%; (e) (i) 1.1 bar H2, Ra−Ni, MeOH/THF, rt, 15 h; (ii)
2,4-dichloro-6-methoxy-1,3,5-triazine, 2,6-lutidine, THF, 0 °C, 0.5 h
then rt, 5 h, yield quantitative; (f) 7 M NH3, MeOH, rt, 4.25 h, yield
52%.
(8) Daigle, S. R.; Olhava, E. J.; Therkelsen, C. A.; Majer, C. R.;
Sneeringer, C. J.; Song, J.; Johnston, L. D.; Scott, M. P.; Smith, J. J.;
Xiao, Y.; Jin, L.; Kuntz, K. W.; Chesworth, R.; Moyer, M. P.; Bernt, K.
M.; Tseng, J. C.; Kung, A. L.; Armstrong, S. A.; Copeland, R. A.;
Richon, V. M.; Pollock, R. M. Selective killing of mixed lineage
leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer
Cell 2011, 20, 53−65.
(9) Daigle, S. R.; Olhava, E. J.; Therkelsen, C. A.; Basavapathruni,
A.; Jin, L.; Boriack-Sjodin, P. A.; Allain, C. J.; Klaus, C. R.; Raimondi,
A.; Scott, M. P.; Waters, N. J.; Chesworth, R.; Moyer, M. P.;
Copeland, R. A.; Richon, V. M.; Pollock, R. M. Potent inhibition of
DOT1L as treatment of MLL-fusion leukemia. Blood 2013, 122,
1017−1025.
(10) Stein, E. M.; Garcia-Manero, G.; Rizzieri, D. A.; Tibes, R.;
Berdeja, J. G.; Savona, M. R.; Jongen-Lavrenic, M.; Altman, J. K.;
Thomson, B.; Blakemore, S. J.; Daigle, S. R.; Waters, N. J.; Suttle, A.
B.; Clawson, A.; Pollock, R.; Krivtsov, A.; Armstrong, S. A.;
DiMartino, J.; Hedrick, E.; Lowenberg, B.; Tallman, M. S. The
DOT1L inhibitor pinometostat reduces H3K79 methylation and has
modest clinical activity in adult acute leukemia. Blood 2018, 131,
2661−2669.
target gene suppression and leukemic cell death or differ-
entiation, underlines the need for extreme target inhibition to
achieve the desired functional consequences. With the better
understanding of MLL-rearranged leukemia, alternative treat-
ment strategies are emerging.16 Even if more potent DOT1L
inhibitors can be discovered, we expect that combination
treatment will be needed in order to fully exploit the potential
of DOT1L inhibition in mixed lineage leukemia and achieve
substantial clinical benefit in a large proportion of patients.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
S
PK compound 10 Figure S1, selectivity HMT panel
Table S4, summary of reported activities, HTS assay
principle, and experimental procedures (PDF)
(11) Chen, C.; Zhu, H.; Stauffer, F.; Caravatti, G.; Vollmer, S.;
Machauer, R.; Holzer, P.; Mobitz, H.; Scheufler, C.; Klumpp, M.;
Tiedt, R.; Beyer, K. S.; Calkins, K.; Guthy, D.; Kiffe, M.; Zhang, J.;
Gaul, C. Discovery of Novel Dot1L Inhibitors through a Structure-
Based Fragmentation Approach. ACS Med. Chem. Lett. 2016, 7, 735−
740.
AUTHOR INFORMATION
Corresponding Author
ORCID
■
(12) Mobitz, H.; Machauer, R.; Holzer, P.; Vaupel, A.; Stauffer, F.;
Ragot, C.; Caravatti, G.; Scheufler, C.; Fernandez, C.; Hommel, U.;
Tiedt, R.; Beyer, K. S.; Chen, C.; Zhu, H.; Gaul, C. Discovery of
Potent, Selective, and Structurally Novel Dot1L Inhibitors by a
Fragment Linking Approach. ACS Med. Chem. Lett. 2017, 8, 338−
343.
(13) Scheufler, C.; Mobitz, H.; Gaul, C.; Ragot, C.; Be, C.;
Fernandez, C.; Beyer, K. S.; Tiedt, R.; Stauffer, F. Optimization of a
Fragment-Based Screening Hit toward Potent DOT1L Inhibitors
́
́
Notes
The authors declare the following competing financial
interest(s): Authors are shareholders of Novartis and/or
employees of Novartis.
PyMol was used for structural visualization and figure
preparation.17
E
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX