Theoretical and Natural Science
- The Open Access Proceedings Series for Conferences
Theoretical and Natural Science
Vol. 23, 20 December 2023
Open
Access | Article
The application of small molecule drug in clinical trial
* Author to whom correspondence should be addressed.
Abstract
In the most recent century, small molecule drugs have become prominent in treating different illnesses and diseases. These small molecule drugs, ranging between 0.1 and 1 kDa in size, have been specifically chemically synthesized not to trigger immune responses. In addition to their nonimmunogenic nature, small molecules tend to possess a low molecular weight and a well-defined structure. They are process-independent, stable, and completely characterizable.
Keywords
Small Molecule Drug, Clinical Trial, Kinases
References
1. Trusheim M R, Aitken M, Berndt E R. Characterizing Markets for Biopharmaceutical Innovations: Do Biologics Differ from Small Molecules? Social Science Electronic Publishing[2023-07-12].DOI:10.2139/ssrn.1880601.
2. Declerck P J. Biologicals and biosimilars: a review of the science and its implications. Generics and Biosimilars Initiative Journal, 2012, 1(1). DOI:10.5639/gabij.2012.0101.005.
3. Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for predicting human oral bioavailability. Int. J. Mol. Sci. 2012, 13, 6964–6982.
4. Kell, D.B.; Goodacre, R. Metabolomics and systems pharmacology: Why and how to model the human metabolic network for drug discovery. Drug Discov. Today 2014, 19, 171–182.
5. Kirchmair, J.; Williamson, M.J.; Tyzack, J.D.; Tan, L.; Bond, P.J.; Bender, A.; Glen, R.C. Computational prediction of metabolism: Sites, products, SAR, P450 enzyme dynamics, and mechanisms. J. Chem. Inf. Model. 2012, 52, 617–648.
6. Xie, L.; Xie, L.; Kinnings, S.L.; Bourne, P.E. Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Annu. Rev. Pharm. Toxicol. 2012, 52, 361–379.
7. Xu J, Shi P Y, Li H,et al.Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential[J].ACS Infectious Diseases, 2020,.DOI:10.1021/acsinfecdis.0c00052.
8. Dey A, Kang X, Qiu J,et al.Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside.[J].Trends in Pharmacological Sciences, 2016:463-484.DOI:10.1016/j.tips.2016.03.001.
9. Hoelder S, Clarke P A, Workman P. Discovery of small molecule cancer drugs: Successes, challenges, and opportunities[J]. Molecular oncology, 2012(2):6.
10. Kaufmann, S.H., 2008. Paul Ehrlich: founder of chemotherapy. Nat. Rev. Drug Discov. 7, 373.
11. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. N Engl J Med. 2016;374:1243–52.
12. Zhou,Wei,Wang,et al.IJMS, Vol. 17, Pages 246: Systems Pharmacology in Small Molecular Drug Discovery[J]. 2016
13. Quentmeier, H., Reinhardt, J., Zaborski, M. & Drexler, H. G. FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 17, 120–124 (2003).
14. Tallman, M. S., Gilliland, D. G. & Rowe, J. M. Drug therapy for acute myeloid leukemia. Blood 106, 1154–1163 (2005).
15. Stone, R. M. et al. Midostaurin plus chemotherapy for acute myeloid leukemiawith a FLT3 mutation. N. Engl. J. Med. 377, 454–464 (2017).
16. Zarrinkar, P. P. et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114, 2984–2992 (2009).
17. Cortes, J. et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 19, 889–903 (2018).
18. Sutamtewagul, G. & Vigil, C. E. Clinical use of FLT3 inhibitors in acute myeloid leukemia. Onco Targets Ther. 11, 7041–7052 (2018).
19. Lim, S. H., Dubielecka, P. M. & Raghunathan, V. M. Molecular targeting in acute myeloid leukemia. J. Transl. Med. 15, 183 (2017).
20. Miller, G. D., Bruno, B. J. & Lim, C. S. Resistant mutations in CML and Ph(+)ALL - role of ponatinib. Biologics 8, 243–254 (2014).
21. Quintas-Cardama, A. & Cortes, J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113, 1619–1630 (2009).
22. Klein, F. et al. The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells. J. Exp. Med. 199, 673–685 (2004).
23. Deininger, M., Buchdunger, E. & Druker, B. J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105, 2640–2653 (2005).
24. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).
25. Hochhaus, A. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190–2196 (2002).
26. Hantschel, O., Grebien, F. & Superti-Furga, G. The growing arsenal of ATP- competitive and allosteric inhibitors of BCR-ABL. Cancer Res. 72, 4890–4895 (2012).
27. Azam, M., Latek, R. R. & Daley, G. Q. Mechanisms of autoinhibition and STI-571/ imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112, 831–843 (2003).
28. Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7, 129–141 (2005).
29. Puttini, M. 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. 66, 11314–11322 (2006).
30. Sawyers, C. L. Even better kinase inhibitors for chronic myeloid leukemia. N. Engl. J. Med. 362, 2314–2315 (2010).
31. O’Hare, T. et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 65, 4500–4505 (2005).
32. O’Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.Cancer Cell 16, 401–412 (2009).
33. Wylie, A. A. et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 543, 733–737 (2017).
34. Yokota, A. et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor,suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood 109, 306–314 (2007).
35. Tanaka, S. & Baba, Y. B cell receptor signaling. Adv. Exp. Med. Biol. 1254, 23–36 (2020).
36. Davids, M. S. & Brown, J. R. Ibrutinib: a first in class covalent inhibitor of Bruton’s tyrosine kinase. Future Oncol. 10, 957–967 (2014).
37. Akinleye, A. et al. Ibrutinib and novel BTK inhibitors in clinical development. J. Hematol. Oncol. 6, 59 (2013).
38. Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).
39. Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).
40. Wu, J., Liu, C., Tsui, S. T. & Liu, D. Second-generation inhibitors of Bruton tyrosine kinase. J. Hematol. Oncol. 9, 80 (2016).
41. Guo, Y. et al. Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 62, 7923–7940 (2019).
42. Park, S. Y. & Kim, J. S. A short guide to histone deacetylases including recent progress on class II enzymes. Exp. Mol. Med. 52, 204–212 (2020).
43. Delcuve, G. P., Khan, D. H. & Davie, J. R. Roles of histone deacetylases in epi- genetic regulation: emerging paradigms from studies with inhibitors. Clin. Epi-genet. 4, 5 (2012).
44. Li, Y. & Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6, a026831 (2016).
45. Abaza, Y. M. et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer 123, 4851–4859 (2017).
46. Stoddard, B. L., Dean, A. & Koshland, D. E. Jr. Structure of isocitrate dehy- drogenase with isocitrate, nicotinamide adenine dinucleotide phosphate, and calcium at 2.5-A resolution: a pseudo-Michaelis ternary complex. Biochemistry 32, 9310–9316 (1993).
47. Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010).
48. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2- hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
49. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
50. Dang, L., Jin, S. & Su, S. M. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387–397 (2010).
51. Kim, E. S. Enasidenib: first global approval. Drugs 77, 1705–1711 (2017).
52. Galkin, M. & Jonas, B. A. Enasidenib in the treatment of relapsed/refractory acute myeloid leukemia: an evidence-based review of its place in therapy. Core Evid. 14, 3–17 (2019).
53. Kantarjian, H. et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106, 1794–1803 (2006).
54. Silverman, L. R. et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429–2440 (2002).
55. Olino, K., Park, T. & Ahuja, N. Exposing hidden targets: combining epigenetic and immunotherapy to overcome cancer resistance. Semin. Cancer Biol. 65, 114–122 (2020).
56. Laubach, J. P., Moreau, P., San-Miguel, J. F. & Richardson, P. G. Panobinostat for the treatment of multiple myeloma. Clin. Cancer Res. 21, 4767–4773 (2015).
57. Knight, T. et al. A delicate balance - The BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics. Biochem. Pharm. 162, 250–261 (2019). 501. Warren, C. F. A., Wong-Brown, M. W. & Bowden, N. A. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis. 10, 177 (2019).
58. Huang, K. et al. BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. Cell Res. 29, 942–952 (2019).
59. Lampson, B. L. & Davids, M. S. The development and current use of BCL-2 inhibitors for the treatment of chronic lymphocytic leukemia. Curr. Hematol. Malig. Rep. 12, 11–19 (2017).
60. Stilgenbauer, S. et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 17, 768–778 (2016).
61. Guerra, V. A., DiNardo, C. & Konopleva, M. Venetoclax-based therapies for acute myeloid leukemia. Best Pr. Res. Clin. Haematol. 32, 145–153 (2019).
62. Caenepeel, S. et al. AMG 176, a selective MCL1 inhibitor, is effective in hema- tologic cancer models alone and in combination with established therapies. Cancer Discov. 8, 1582–1597 (2018).
63. McBride, A. et al. The role of inhibition of apoptosis in acute leukemias and myelodysplastic syndrome. Front. Oncol. 9, 192 (2019).
64. Tron, A. E. et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun. 9, 5341 (2018). 519. Yalniz, F. F. & Wierda, W. G. Targeting BCL2 in chronic lymphocytic leukemia and other hematologic malignancies. Drugs 79, 1287–1304 (2019).
65. Pak, E. & Segal, R. A. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev. Cell 38, 333–344 (2016).
66. Tukachinsky, H., Petrov, K., Watanabe, M. & Salic, A. Mechanism of inhibition of the tumor suppressor Patched by Sonic Hedgehog. Proc. Natl Acad. Sci. USA 113, E5866–e5875 (2016).
67. Dlugosz, A., Agrawal, S. & Kirkpatrick, P. Vismodegib. Nat. Rev. Drug Discov. 11, 437–438 (2012).
68. Xie, H., Paradise, B. D., Ma, W. W. & Fernandez-Zapico, M. E. Recent advances in the clinical targeting of Hedgehog/GLI signaling in cancer. Cells. 8, 394 (2019).
69. Girardi, D., Barrichello, A., Fernandes, G. & Pereira, A. Targeting the Hedgehog pathway in cancer: current evidence and future perspectives. Cells 8, 153 (2019).
70. Schram, A. M., Chang, M. T., Jonsson, P. & Drilon, A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat. Rev. Clin. Oncol. 14, 735–748 (2017).
71. Pottier, C. et al. Tyrosine kinase inhibitors in cancer: breakthrough and chal- lenges of targeted therapy. Cancers 12, 731 (2020).
72. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).
73. Chau, V. & Bilusic, M. Pembrolizumab in combination with axitinib as first-line treatment for patients with renal cell carcinoma (RCC): evidence to date. Cancer Manag. Res. 12, 7321–7330 (2020).
74. Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal- cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
75. Schapira, L. Simple rules can improve prognostic accuracy. J. Clin. Oncol. 29, 347–349 (2011).
76. Beck, A. et al. The next generation of antibody-drug conjugates comes of age. Discov. Med. 10, 329–339 (2010).
77. An, S. & Fu, L. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine 36, 553–562 (2018).
Data Availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Authors who publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open Access Instruction).
- Volume Title
- Proceedings of the 3rd International Conference on Biological Engineering and Medical Science
- ISBN (Print)
- 978-1-83558-219-0
- ISBN (Online)
- 978-1-83558-220-6
- Published Date
- 20 December 2023
- Series
- Theoretical and Natural Science
- ISSN (Print)
- 2753-8818
- ISSN (Online)
- 2753-8826
- DOI
- 10.54254/2753-8818/23/20231031
- Copyright
- 20 December 2023
- Open Access
- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited