Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development
Abstract
:1. Introduction
1.1. AP23464: Ponatinib Precursor
1.2. Conformational Restriction of the Spacer as a Medicinal Chemical Tool: Insertion of the Ethylene Group
1.3. The Insertion of Arylamines: Targeting the Deep Hydrophobic Pocket of the Enzyme
Learning from IMT and NLT: The Importance of the Position of the Amide Group
1.4. Focus on the Selective Hydrophobic Pocket in the Deep Region of the Kinase: The Terminal Aromatic Ring of Compounds
1.5. Large Structural Change in the T315I Mutation: The Introduction of Acetylene as a Spacer
1.6. Final Adjustments: Focus on the Hinge Region and ADMET Properties
1.7. Ponatinib (PNT)
- ✓
- Adeninomimetic-hinge core (imidazolo[1,2-b]pyridazine): To mimic the adenine nucleus of ATP, fused heteroaromatic (nitrogenated) rings, culminating in imidazolo[1,2-b]pyridazine, were explored. The imidazole fits into the hinge region through a hydrogen bond-like interaction with Met318, establishing van der Waals interactions with residues Met318 and Phe317. The pyridazine ring establishes hydrophobic interactions with specific amino acids, such as Phe382 in the DFG triad and Tyr253 in the P-loop region (Figure 19) [81].
- ✓
- Gatekeeper-linker 1 (ethynyl group): The SAR analysis of PNT revealed that the conformational restriction of the linker plays a crucial role in its ability to inhibit ABL1T315I. This may be due to steric relief to the gatekeeper residue (Ile315), allowing access to both the hinge region and the deeper region of the enzyme in the selective hydrophobic pocket provided by the inactive DFG-out conformation (as shown in Figure 17) [81].
- ✓
- Hydrophobic pocket-ring A (arene moiety): This ring occupies the hydrophobic cavity of the BCR-ABL1 enzyme located behind the gatekeeper residue (Figure 19). The presence of the methyl group is essential because it allows access to the deeper region of the enzyme through a conformational restriction in the IMT, NLT, and PNT inhibitors. Changing positions or removing them can reduce their biological activity [81].
- ✓
- DFG-linker 2 interaction region (amide group): This peptide bond between aromatic rings A and B results in crucial hydrogen bond-type interactions in the enzyme between the carbonyl oxygen of the amide and the Asp381 residue and the NH group with the Glu286 residue. These interactions anchor the inhibitor in the active site (Figure 19) [81].
- ✓
- Selective hydrophobic pocket-ring B (arene moiety): This pocket-ring makes hydrophobic contact with the biomacromolecule. The presence of the trifluoromethyl group allows the exploration of new hydrophobic contacts in the deep region of the enzyme [81].
- ✓
- Terminal residue or Tail (N-methylpiperazine moiety): Although the authors do not consider it one of the main fragments of PNT, crucial hydrogen bond-like interactions are established between the methylpiperazine group and His361 and Ile360 residues of the ABL1T315I kinase structure (Figure 19) [81].
2. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compound | IC50 (ABL1T315I) (nM) | cLogP a |
---|---|---|
AP23464 | >5000 | 3.99 |
AP23848 | 5.1 | 5.36 |
AP23846 | 6.4 | 4.20 |
AP23980 | 297 | 4.62 |
Compound | IC50 (ABL1WT) a (nM) | cLogP b |
---|---|---|
AP23464 | 61 | 3.99 |
1 | 15.8 | 4.67 |
2 | 3.58 | 3.68 |
Compound | IC50 (ABL1WT) a (nM) | IC50 (SRC) (nM) | cLogP b |
---|---|---|---|
AP23464 | 61 | ≤1 | 3.99 |
2 | 3.58 | - | 4.67 |
3 | 96 | 300 | 4.10 |
4 | 25 | 52 | 4.13 |
Compound | IC50 (K562) a | IC50 (Ba/F3) (BCR-ABL1WT) a | IC50 (Ba/F3) (Parenteral) a | IC50 (ABL1WT) a | IC50 (SRC) a | cLogP b |
---|---|---|---|---|---|---|
4 | 67 | 47 | >1000 | 25 | 52 | 4.13 |
5 | 95 | 57 | 7857 | 74 | 91 | 4.57 |
Compound | IC50 (ABL1WT) (nM) | IC50 (SRC) (nM) |
---|---|---|
5 | 74 | 91 |
6 | 23 | 74 |
Compound | IC50 (Ba/F3) (BCR-ABL1T315I) a | IC50 (Ba/F3) (Parenteral) a | IC50 (ABL1WT) a | IC50 (ABL1T315I) a | IC50 (SRC) a | cLogP b |
---|---|---|---|---|---|---|
6 | - | 4353 | 23 | - | 11 | 3.92 |
7 | - | 4894 | 20 | - | 7 | 3.12 |
8 | 298 | 7120 | 13 | 542 | 8.0 | 4.36 |
9 | 422 | 6455 | 25 | 478 | 7.6 | 4.71 |
Compound | IC50 (ABL1T315I) a | IC50 T315I (Ba/F3) a | IC50 (ABL1WT) a | cLogP b |
---|---|---|---|---|
AP24163 | 478 | 422 | 25 | 3.99 |
10 | 386 | 295 | 1.6 | 3.41 |
Compound | IC50 (ABL1WT) a | IC50 (ABL1T315I) a | cLogP b |
---|---|---|---|
7 | 20 | 14142 | 3.12 |
11 | 23 | 15513 | 3.74 |
12 | 30 | 524 | 3.32 |
13 | 28 | 359 | 3.78 |
Compound | IC50 (ABL1WT) a | IC50 (ABL1T315I) a | F% |
---|---|---|---|
15 | 2.3 | 1216 | 5.5 |
16 | 26 | 102 | 42.4 |
17 | 45 | 168 | ND |
18 | 26 | 185 | ND |
19 | 9 | 56 | 29.0 |
20 | 69 | 639 | ND |
21 | 2.3 | 9 | 16.7 |
22 | 8.6 | 40 | 18.2 |
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Nascimento, M.; Moura, S.; Parra, L.; Vasconcellos, V.; Costa, G.; Leite, D.; Dias, M.; Fernandes, T.V.A.; Hoelz, L.; Pimentel, L.; et al. Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development. Pharmaceuticals 2024, 17, 1361. https://doi.org/10.3390/ph17101361
Nascimento M, Moura S, Parra L, Vasconcellos V, Costa G, Leite D, Dias M, Fernandes TVA, Hoelz L, Pimentel L, et al. Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development. Pharmaceuticals. 2024; 17(10):1361. https://doi.org/10.3390/ph17101361
Chicago/Turabian StyleNascimento, Mayara, Stefany Moura, Lidia Parra, Valeska Vasconcellos, Gabriela Costa, Debora Leite, Maria Dias, Tácio Vinício Amorim Fernandes, Lucas Hoelz, Luiz Pimentel, and et al. 2024. "Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development" Pharmaceuticals 17, no. 10: 1361. https://doi.org/10.3390/ph17101361
APA StyleNascimento, M., Moura, S., Parra, L., Vasconcellos, V., Costa, G., Leite, D., Dias, M., Fernandes, T. V. A., Hoelz, L., Pimentel, L., Bastos, M., & Boechat, N. (2024). Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development. Pharmaceuticals, 17(10), 1361. https://doi.org/10.3390/ph17101361