Small-Molecule Immuno-Oncology Therapy: Advances, Challenges and New Directions

Author(s): Shulun Chen, Zilan Song, Ao Zhang*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 3 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Oncology immunotherapy has gained significant advances in recent years and benefits cancer patients with superior efficacy and superior clinical responses. Currently over ten immune checkpoint antibodies targeting CTLA-4 and PD-1/PD-L1 have received regulatory approval worldwide and over thousands are under active clinical trials. However, compared to the rapid advance of Monoclonal Antibody (mAb), studies on immunotherapeutic small molecules have far lagged behind. Small molecule immunotherapy not only can target immunosuppressive mechanisms similar to mAbs, but also can stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAbs are unable to access. Therefore, small molecule immunotherapy can provide an alternative treatment modality either alone or complementary to or synergistic with extracellular checkpoint mAbs to address low clinical response and drug resistance. Fortunately, remarkable progress has achieved recently in the pursuit of small molecule immunotherapy. This review intends to provide a timely highlight on those clinically investigated small molecules targeting PD-1/PD-L1, IDO1, and STING. The most advanced IDO1 inhibitor epacadostat have been aggressively progressed into multiple clinical testings. Small molecule PD-1/PD-L1 inhibitors and STING activators are still in a premature state and their decisive application needs to wait for the ongoing clinical outcomes. Since no small molecule immunotherapy has been approved yet, the future research should continue to focus on discovery of novel small molecules with distinct chemo-types and higher potency, identification of biomarkers to precisely stratify patients, as well as validation of many other immune-therapeutic targets, such as LAG3, KIRs, TIM-3, VISTA, B7-H3, and TIGIT.

[1]
Finn, O.J. Immuno-oncology: Understanding the function and dysfunction of the immune system in cancer. Ann. Oncol., 2012, 23(Suppl. 8), Viii6-9,.
[2]
Sondak, V.K.; Smalley, K.S.M.; Kudchadkar, R.; Grippon, S.; Kirkpatrick, P. Ipilimumab. Nat. Rev. Drug Discov., 2011, 10, 411-412.
[3]
Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; Larkin, J.; Lorigan, P.; Neyns, B.; Blank, C.U.; Hamid, O.; Mateus, C.; Shapira-Frommer, R.; Kosh, M.; Zhou, H.; Ibrahim, N.; Ebbinghaus, S.; Ribas, A. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med., 2015, 372, 2521-2532.
[4]
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M.J.; Felip, E.; Lee, J.S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J.C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunceford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015, 372, 2018-2028.
[5]
Gong, J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. Immunother. Cancer, 2018, 6, 8.
[6]
Tang, J.; Yu, J.X.; Hubbard-Lucey, V.M. Neftelinov, S.T.; Hodge, J.P.; Lin, Y. Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov., 2018, 17, 854-855.
[7]
Adams, J.L.; Smothers, J.; Srinivasan, R.; Hoos, A. Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov., 2015, 14, 603-622.
[8]
Dhanak, D.; Edwards, J.P.; Nguyen, A.; Tummino, P.J. Small molecule targets in immuno-oncology. Cell Chem. Biol., 2017, 24, 1148-1157.
[9]
Kerr, W.G.; Chisholm, J.D. The next generation of immunotherapy for cancers: small molecules could make big waves. J. Immunol., 2019, 202, 11-19.
[10]
Toogood, P.L. Small molecule immune-oncology therapeutic agent. Bioorg. Med. Chem. Lett., 2018, 28, 319-329.
[11]
Wang, T.; Wu, X.; Guo, C.; Zhang, K.; Xu, J.; Li, Z.; Jiang, S. Development of inhibitors of the programmed cell death-1/programmed cell death-ligand 1 signaling pathway. J. Med. Chem., 2019, 62, 1715-1730.
[12]
Huck, B.R.; Kotzner, L.; Urbahns, K. Small molecules drive big improvements in immuno-oncology therapies. Angew. Chem. Int. Ed., 2018, 57, 4412-4428.
[13]
Cheng, B.; Yuan, W-E.; Su, J.; Liu, Y.; Chen, J. Recent advances in small molecule based cancer immunotherapy. Eur. J. Med. Chem., 2018, 157, 582-598.
[14]
Guzik, K.; Zak, K.M.; Grudnik, P.; Magiera, K.; Musielak, B.; Torner, R.; Skalniak, L.; Domling, A.; Dubin, G.; Holak, T.A. Small molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) interaction via transiently induced protein states and dimerization of PD-L1. J. Med. Chem., 2017, 60, 5857-5867.
[15]
Magiera-Mularz, K.; Skalniak, L.; Zak, K.M.; Musielak, B.; Rudzinska-Szostak, E.; Berlicki, L.; Kocik, J.; Grudnik, P.; Sala, D.; Zarganes-Tzitzikas, T.; Shaabani, S.; Domling, A.; Dubin, G.; Holak, T.A. Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint. Angew. Chem. Int. Ed., 2017, 56, 13732-13735.
[16]
Skalniak, L.; Zak, K.M.; Guzik, K.; Magiera, K.; Musielak, B.; Pachota, M.; Szelanzek, B.; Kocik, J.; Grudnik, P.; Tomala, M.; Krzanik, S.; Pyrc, K.; Domling, A.; Dubin, G.; Holak, T.A. Small-molecule inhibitors of PD-1/PDL1 immune checkpoint alleviate the PDL1-induced exhaustion of T-cells. Oncotarget, 2017, 8(42), 72167-72181.
[17]
Sasikumar, P.G.N. 1,2,4-oxadiazole derivatives as immunomodulators. Bristol-Myers Squibb, WO2015033299, A1 2015.
[18]
Zhu, M.M.T.; Dancsok, A.R.; Nielsen, T.O. Indoleamine dioxygenase inhibitors: Clinical rationale and current development. Curr. Oncol. Rep., 2019, 21, 2-14.
[19]
Cheong, J.E.; Sun, L. Targeting the IDO/TDO2-KYN-AhR pathway for cancer immunotherapy-challenges and opportunities. Trends Pharmacol. Sci., 2018, 39(3), 307-325.
[20]
Komiya, T.; Huang, C.H. Updates in the clinical development of Epacadostat and other indoleamine 2,3-dioxygenase 1 inhibitor (IDO1) for human cancers. Front. Oncol., 2018, 8, 423-429.
[21]
Muller, A.J.; Manfredi, M.G.; Zakharia, Y.; Prendergast, G.C. Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin. Immunopathol., 2019, 41, 41-48.
[22]
Nayak-Kapoor, A.; Hao, Z.; Sadek, R.; Dobbins, R.; Marshall, L.; Vahanian, N.N.; Ramsey, W.J.; Kennedy, E.; Mautino, M.R.; Link, C.J.; Salphati, L.; McCall, B.; Pirzkall, A.; Munn, D.H.; Janik, J.E.; Khleif, S.N. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J. Immunother. Cancer, 2018, 6, 61.
[23]
Gomes, B.; Driessens, G.; Bartlett, D.; Cai, D.; Cauwenberghs, S. Denies, S.; Dillon, C.P.; Li, W.; Maegley, K.; Rabolli, V.; Wythes, M.; Yao, L.-C.; Zheng, X.; Tumang, J.; Ktaus, M. Characterization of the selective indoleamine 2,3-dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy. Mol. Cancer Ther., 2018, 17(12), 2530-2542.
[24]
Rahanjuli, J.; M., Pesiridis G.S.; Yang, J.; Concha, N.; Singhaus, R.; Zhang, S.Y.; Tran, J.L.; Moore, P.; Lehmann, S.; Eberl, H.C.; Muelbaier, M.; Schneck, J.L.; Clemens, J.; Adam, M.; Mehlmann, J.; Romano, J.; Morales, A.; Kang, J.; Leister, L.; Graybill, T.L.; Charnley, A.K.; Ye, G.; Nevins, N.; Behnia, K.; Wolf, A.I.; Bantscheff, M.; Bergamini, G.; Reilly, M.A.; Lian, Y.; Duffy, K. J.; Adams, J.; Foley, K.P.; Gough, P.J.; Marquis, R.W.; Smothers, J.; Hoos, A.; Bertin J. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature, 2018, 564(7736), 439-443.
[25]
Banerjee, M.; Middya, S.; Bbasu, S. Small molecule modulators of human STING. Curadev. Pharma. Pvt. Ltd., 2018, WO2018(234808), A1.
[26]
Dempke, W.C.M.; Fenchel, K.; Uciechowski, P.; Dale, S.P. Second- and third-generation drugs for immuno-oncology treatment-The more the better. Eur. J. Cancer, 2017, 74, 55-72.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 3
Year: 2019
Page: [180 - 185]
Pages: 6
DOI: 10.2174/1568026619666190308131805
Price: $58

Article Metrics

PDF: 38
HTML: 6