Small-Molecule Immuno-Oncology Therapy: Advances, Challenges and New Directions
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Published:2019-03-28
Issue:3
Volume:19
Page:180-185
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ISSN:1568-0266
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Container-title:Current Topics in Medicinal Chemistry
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language:en
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Short-container-title:CTMC
Author:
Chen Shulun1, Song Zilan1, Zhang Ao1
Affiliation:
1. CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
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.
Funder
Strategic Leading Project A on Precision Medicine of the Chinese Academy of Sciences Shanghai Commission of Science and Technology Key Program of the Frontier Science of the Chinese Academy of Sciences National Program on Key Basic Research Project of China National Natural Science Foundation of China
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,General Medicine
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