Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon
Abstract
:1. Introduction
2. Altered Cell Proliferation in Acute Leukemias
2.1. FLT3 Alterations in Acute Leukemia: A Driver of Cell Proliferation
2.2. Cell Cycle Regulation in Hematopoietic Cells and in Acute Leukemias
2.3. Cell Cycle Alterations in Acute Leukemia
3. Novel Molecules Targeting Proliferative Mechanisms in Acute Leukemias
3.1. Novel Molecules Targeting FLT3
3.2. Targeting Other Proliferative Signals in AML
3.3. Novel Compounds with Unknown Targets That Inhibit Acute Leukemia Cell Proliferation
3.4. Novel Molecules Targeting the Cell Cycle Machinery
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Molecule. | Target(s) | Disease(s) | IC50 /GI50 | Reference | SAR/Docking Studies |
---|---|---|---|---|---|
5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7c) | FLT3, FLT3-ITD | AML | MV4-11: 95.51 ± 1.16 nM MOLM-13: 61.9 ± 2.45 nM | [54] | Yes |
4-((6,7-dimethoxyquinoline- 4-yl)oxy)aniline derivatives (compound 12c) | FLT3 | AML | MV4-11: 8.29 ± 0.24 µM HL-60: 14.16 ± 0.22 µM | [55] | Yes |
4-((6,7-dimethoxyquinoline- 4-yl)oxy)aniline derivatives (compound 12g) | FLT3 | AML | MV4-11: 5.80 ± 0.42 µM HL-60: 8.91 ± 0.66 µM | [55] | Yes |
4-azaaryl-N-phenylpyrimidin-2-amine derivative (compound 12b) | FLT3, FLT3-ITD and their mutants | AML | MV4-11: 0.074 ± 0.010 µM MOLM-13 0.023 ± 0.001 µM | [56] | Yes |
4-azaaryl-N-phenylpyrimidin-2-amine derivative (compound 12r) | FLT3, FLT3-ITD and their mutants | AML | MV4-11: 0.017 ± 0.012 µM MOLM-13: 0.0004 ± 0.0002 µM | [56] | Yes |
3-aminoisoquinoline analogs (HSW630-1) | FLT3 | AML | MV4-11: 0.15 µM MOLM-14: 0.15 µM | [57] | Yes |
3-amino and 1-aminoisoquinoline benzamides (HSN286) | FLT3, SRC kinases | AML | MV4-11: 0.492 nM MOLM-14: 0.721 nM | [58] | Yes |
N-(3,4-dimethoxybenzyl)-1-phenyl-1H-benzimidazol-5-amine derivative (compound HP1328) | FLT3, FLT3-ITD, c-KIT | AML | Ba/F3 FLT3-ITD: 75.4 ± 3.2 nM MV4-11: 165.0 ± 17.5 nM MOLM-13: 66.8 ± 4.8 nM | [59] | Yes |
pyrimidine-4,6-diamine derivative (compound 13a) | FLT3 | AML | Ba/F3 FLT3-ITD: 131.2 nM MV4-11: 9.9 nM MOLM-14: 24.4 nM MOLM-14D835Y:1842 nM MOLM-14F691L: 1345 nM | [60] | Yes |
amino acid-substituted sunitinib analogue released active compound candidates (20a) | FLT3-ITD | AML | MV4-11: 2.2 ± 0.3 µM | [61] | Yes |
phenylethenylquinazoline derivatives (compound III) | FLT3-ITD, FLT3D835Y, FLT3-ITDD835Y | AML | MV4-11: 0.03 ± 0.00 µM | [62] | Yes |
bis(1H-indol-2-yl)methanones, detivatives (compound 16) | FLT3, FLT3-ITD, FLT3D835Y, RET, ZAK | AML | MV4-11: <0.001 µM MOLM-13: <0.001 µM EOL-1: <0.001 µM | [63] | Yes |
(Z)-N-(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide (compound 17) | FLT3-ITD and its mutants | AML | MV4-11: 23.5 ± 1.2 nM MOLM-13: 35.5 ± 2.1 nM Ba/F3 FLT3-ITD: 12.7 ± 0.1 nM Ba/F3 FLT3-ITDD835Y: 36.7 ± 0.7 nM Ba/F3 FLT3-ITDD835V: 26.8 ± 1.5 nM Ba/F3 FLT3-ITDF691L: 43.6 ± 3.1 nM | [64] | Yes |
imidazo[1,2-a]pyridine-thiophene derivative (compound 5o) | FLT3 and its mutants | AML | MOLM-14: 0.52 ± 0.062 µM MOLM-14 FLT3-ITDD835Y: 0.53 ± 0.022 µM MOLM-14 FLT3-ITDF691L: 0.57 ± 0.058 µM | [65] | Yes |
2-Aminopyrimidine derivative (compound 30) | FLT3, TRKA, Aurora A | AML | MV4-11: 3.20 ± 0.77 nM Ba/F3 FLT3-ITD: 23.32 ± 8.27 nM Ba/F3 FLT3D835V: 1.41 ± 0.11 nM Ba/F3 FLT3D835F: 5.02 ± 0.87 nM Ba/F3 FLT3F691L: 28.84 ± 5.01 nM Ba/F3 FLT3-ITDD835Y: 19.23 ± 10.46 nM Ba/F3 FLT3-ITDF691L: 99.62 ± 3.22 nM | [66] | Yes |
2-Aminopyrimidine derivative (compound 36) | FLT3, TRKA, Aurora A | AML | MV4-11: 0.75 ± 0.11 nM Ba/F3 FLT3-ITD: 0.84 ± 0.33 nM Ba/F3 FLT3D835V: 1.29 ± 0.10 nM Ba/F3 FLT3D835F: 0.16 ± 0.03 nM Ba/F3 FLT3F691L: 3.56 ± 0.48 nM Ba/F3 FLT3-ITDD835Y: 1.71 ± 0.54 nM Ba/F3 FLT3-ITDF691L: 14.50 ± 1.02 nM | [66] | Yes |
1H-pyrazole-3-carboxamide derivatives (compound 8t) | FLT3, CDKs, KDR/VEGFR2, ERK7, FLT1, FLT4, GSK3 | AML, T-ALL | MV4-11: 1.22 nM HL-60 1.15 µM CCRF-CEM: 0.22 µM MOLT-4 0.08 µM | [67] | Yes |
Molecule | Target(s) | Disease(s) | IC50 /GI50 | Cell Cycle Arrest (Phase, Model, Dose, Time Point) | Reference(s) | SAR/Docking Studies |
---|---|---|---|---|---|---|
N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335, compound 27) | FLT3-ITD, PDGFRβ, HPK1, CSF1R, PDGFRα, c-KIT | AML | MV4-11: 0.284 ± 0.018 µM MOLM-13: 0.466 ± 0.026 µM MOLM-14: 0.343 ± 0.025 µM | G0/G1, MV4-11: 0.1–3 µM, 24 h MOLM-13: 0.1–3 µM, 12 h MOLM-14: 0.3–3 µM, 24 h | [68] | Yes |
pyrrolo[2,3-d]pyrimidine derivatives (compound 9u) | FLT3-ITD, PDGFRα, ABL1 and their mutants, HCK, LCK, RET, LYN, MET, MER, TIE2 | AML | MV4-11: 0.089 ± 0.001 nM MOLM-13: 0.022 ± 0.003 nM Ba/F3 FLT3-ITD: 0.92 ± 0.01 nM Ba/F3 FLT3-ITDD835Y: 20.71 ± 2.32 nM Ba/F3 FLT3-ITDF691L: 12.99 ± 0.87 nM |
G0/G1
MV4-11: 1–30 nM, 24 h MOLM-13: 3–30 nM, 24 h | [69] | Yes |
8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (HSD1169, compound 10) | FLT3, FLT3-ITD and its mutants, LRRK2, MELK, DYRK1B, CLK1, TRKC, MNK2, TOPK, ROCK2, MSK2, p70S6K, PKG1a, CDK2/Cyclin A1 | AML | MV4-11: 5.4 nM MOLM-14: 4.9 nM MOLM-13 FLT3-ITDD835Y: 5.1 nM | G1, MV4-11: 62.5 nM, 48–72 h | [70,71] | Yes |
8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine derivative (compound 49) | FLT3, FLT3-ITD and its mutants, LRRK2, MELK, DYRK1B, CLK1, TRKC | AML | MV4-11: 0.070 µM MOLM-13: 0.068 µM MOLM-14: 0.026 µM MOLM14 FLT3D835Y: 0.036 µM MOLM14 FLT3F691L: 0.053 µM Ba/F3 FLT3-ITD: 0.062 µM | G1, MV4-11: 20–500 nM, 24 h | [71] | Yes |
O-methylated flavonol (compound 11) | FLT3, other kinases | AML, ALL | MOLM-13: 2.65 ± 0.28 μM MV4-11: 1.99 ± 0.25 μM HL-60: 12 ± 4.39 µM MOLT-4: 7.95 ± 1.9 µM | G0/G1, MOLM-13: 3 μM, 16–72 h MV4-11: 3 μM, 16–72 h | [72] | Yes |
Flavonoid derivatives (compound 31) | FLT3, FLT3D835Y, FLT3-ITD | AML | MOLM-13: 2.6 ± 0.20 μM MV4-11: 2.6 ± 0.46 μM | G0/G1 MOLM-13: 3 μM, 72 h MV4-11: 3–30 μM, 72 h | [73] | Yes |
Flavonoid derivatives (compound 32) | FLT3, FLT3D835Y, FLT3-ITD | AML | MOLM-13: 32 5.9 ± 0.58 μM MV4-11: 7.9 ± 0.20 μM | G0/G1 MV4-11: 3–10 μM, 72 h | [73] | Yes |
5,7,4′-trihydroxy-6-methoxyflavone (compound 40) | FLT3, FLT3D835Y, FLT3-ITD | AML | MOLM-13: 40 7.0 ± 0.71 μM MV4-11: 6.8 ± 0.66 μM | G0/G1 MOLM-13: 3 μM, 72 h MV4-11: 3–10 μM, 72 h | [73] | Yes |
Fradcarbazole A derivative (compound 6) | FLT3, c-KIT, CDK2 | AML | MV4-11: 0.32 ± 0.03 µM | G0/G1, MV4-11: 0.15–0.6 μM, 24 h | [74] | No |
3-amine-pyrazole-5-benzimidazole compounds (67) | FLT3-ITD and its mutants | AML | MOLM-13: 9.85 ± 1.03 nM MV4-11: 2.93 ± 0.31 nM Ba/F3 FLT3-ITD: 7.60 ± 0.58 nM Ba/F3 FLT3-ITDF691L: 8.30 ± 0.51 nM Ba/F3 TEL-FLT3D835V, Ba/F3 FLT3-ITDY842H, Ba/F3 FLT3-ITDD835V: <1.50 nM | G1, MV4-11: 10–100 nM, 24 h | [75] | Yes |
6-(pyrimidin-4-yl)- 1H-pyrazolo[4,3-b]pyridine derivative (compound 23k) | FLT3, CDK4 | AML | MV4-11: 70 ± 8 nM | G0/G1, MV4-11: 200 nM, 24 h | [76] | Yes |
1-H-pyrazole-3-carboxamide derivatives (compound 50) | FLT3, CDK2,4,6 | AML | MV4-11: 0.008 ± 0.001 µM | G0/G1, MV4-11: 0.02–0.2 μM, 24 h | [77] | Yes |
pyrido-dipyrimidines (compound 20) | topoisomerase II, FLT3 | AML | HL-60: 0.48 ± 0.08 µM | G2/M, HL-60: 2.26 μM, 24 h | [78] | Yes |
N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines (16a) | FLT3, MNK2 | AML | MV4-11: 0.60 ± 0.10 µM | G1, MV4-11: 4.8 μM, 48 h | [79] | Yes |
Molecule | Target(s) | Disease(s) | IC50 /GI50 | Reference | SAR/Docking Studies |
---|---|---|---|---|---|
Indole scaffold derivative (FD223, compound 13) | PI3Kδ | AML | HL-60: 2.25 μM, MOLM-16: 0.87 μM EOL-1: 2.82 μM KG-1: 5.82 μM | [92] | Yes |
PPARα/γ ligand derivative (compound 17f) | STAT5 | AML | KG1a: 2.638 ± 0.51 μM MV4-11: 3.549 ± 0.47 μM | [93] | Yes |
17f analogs (compounds 7a and 7a’) | STAT5 | AML | KG-1a: 7a, 7.8±0.9 μM 7a’, 6.9±0.8 μM MOLM-13: 7a, 5.4±0.5 μM 7a’, 4.7±1.0 μM | [94] | No |
2,9-bis[4-(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline derivatives (compound 1g–i) | G- quadruplexes | AML | MV4-11: 1g, 2.1 ± 0.5 µM 1h, 1.3 ± 0.3 µM 1i, 1.6 ± 0.4 µM U937: 1 g, 2.0 ± 0.8 µM 1h, 2.0 ± 0.7 µM 1i, 3.0 ± 0.9 µM HL-60: 1 g, 3.0 ± 1.0 µM 1h, 8.0 ± 0.9 µM 1i, 3.0 ± 0.8 µM | [95] | FRET melting experiments and native electrospray mass spectrometry |
biimidazole derivative (BIM-2) | G- quadruplexes | AML | U937: 9.2 μM | [96] | Yes |
Quinizarin quaternary ammonium salt 3 | unknown | AML, T-ALL | HL-60: 1.40 ± 0.81 μM MOLT-4: 2.61 ± 0.15 μM Jurkat: 2.80 ± 0.22 μM | [97] | Yes |
3,5-dimethylisoxazole derivatives (compound 58) | BRD4 | AML | MV4-11: 0.15 ± 0.02 µM HL-60: 1.21 ± 0.02 µM | [98] | Yes |
3-Hydroxyisoindolin-1-one derivate (compound 10e) | BRD4 | AML | MV4-11: 0.420 ± 0.011 µM HL-60: 0.365 ± 0.018 µM | [99] | Yes |
Quinolin-2-one Hit (compound 13-d) | BRPF1 | AML | OCI-AML2: 1.3 µM NOMO-1: 4.6 µM THP-1: 5.7 µM KG-1: 7.0 µM MV4-11: 9.9 µM | [100] | Yes |
Molecule | Target(s) | Disease | IC50 /GI50 | Reference | SAR/Docking Studies |
---|---|---|---|---|---|
3′, 5′-diprenylated chalcone | unknown | Erythroleukemia | HEL: 2.027 ± 0.523 µmol/L | [117] | No |
dithiocarbamate esters of parthenolide (compound 7l) | unknown | AML | KG-1a: 0.7 ± 0.2 μM. HL-60: 1.7 ± 0.5 μM. | [118] | No |
Neglectin derivative (compound 8) | unknown | AML | HL-60: 7.24 ± 0.15 µM | [119] | No |
2,4-dinitrobenzenesulfonamide derivative (S1) | unknown | T-ALL | Jurkat: 6.0 ± 0.4 μM | [120] | No |
Octatetraenylpyrrole (compound 3s) | unknown | T-ALL | CCRF-CEM: 0.27 μM. | [121] | No |
Molecule | Target(s) | Disease(s) | IC50 /GI50 | Reference | SAR/Docking Studies |
---|---|---|---|---|---|
2-carbomethoxy-3-substituted indoles (compound 20) | Tubulin (suggested by cell phenotype) | ALL, AML | CEM: 0.22 µM RS4;11: 0.30 µM | [122] | No |
Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) | Tubulin | T-ALL, B-ALL | CRF-CEM: 244 nM DND41: 210 nM Jurkat: 273 nM HBP-ALL: 94 nM Loucy: 334 nM MOLT-4: 241 nM MOLT-16: 234 nM RPMI8402: 301 nM NALM-16: 272 nM REH: 287 nM | [123] | Yes |
CDK2-PROTAC | CDK2 | AML | MV4-11: 100 nM < IC50 < 1 µM | [124] | Yes |
Diaminopyrimidine derivatives (compound 13) | CHK1 | AML | MV4-11: 0.035 ± 0.007 μM | [125] | Yes |
1-substituted pyrido[4,3-b]carbazole derivatives of olivacine | TP53 restoration | T-ALL | CCFR/CEM: Compound 1: 0.442 ± 0.062 µM Compound 2: 0.520 ± 0.185 µM Compound 3: 0.359 ± 0.109 µM | [126] | No |
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Ghelli Luserna di Rorà, A.; Jandoubi, M.; Martinelli, G.; Simonetti, G. Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon. Molecules 2023, 28, 1224. https://doi.org/10.3390/molecules28031224
Ghelli Luserna di Rorà A, Jandoubi M, Martinelli G, Simonetti G. Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon. Molecules. 2023; 28(3):1224. https://doi.org/10.3390/molecules28031224
Chicago/Turabian StyleGhelli Luserna di Rorà, Andrea, Mouna Jandoubi, Giovanni Martinelli, and Giorgia Simonetti. 2023. "Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon" Molecules 28, no. 3: 1224. https://doi.org/10.3390/molecules28031224