The ups, downs and new trends of IDO1 inhibitors.

Cancer immunotherapy has become an emerging driving force in the development of innovative strategies to fight against cancer. Despite the significant clinical benefits that many cancer patients have gained, the generally average response rate of ~ 20% is far behind the expectation for immune checkpoint inhibitors (ICIs). Combination of ICIs with indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors is considered as an alternative solution and has proved effective in tremendous preclinical studies. However, the failure of phase III ECHO-301/KEYNOTE-252 trial seriously dampened the enthusiasm on the rationality of IDO1-targeting strategy. Fortunately, in spite of the ups and downs in the developmental journey of IDO1 inhibitors, multiple new approaches have been proposed to bridge the gap between lab to the clinic. Here, we review the recent advances in the development of small molecule inhibitors targeting IDO1 especially the new trend of IDO1 inhibitors after ECHO-301 clinical trials, including dual or pan-inhibitors targeting IDO1 and TDO or IDO2, apo-IDO1 inhibitors, IDO1 PROTACs, as well as other IDO1 inhibitors.

Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.

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

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.

Bipolar Electrode Array Embedded in a Polymer Light-Emitting Electrochemical Cell.

A linear array of aluminum discs is deposited between the driving electrodes of an extremely large planar polymer light-emitting electrochemical cell (PLEC). The planar PLEC is then operated at a constant bias voltage of 100 V. This promotes in situ electrochemical doping of the luminescent polymer from both the driving electrodes and the aluminum discs. These aluminum discs function as discrete bipolar electrodes (BPEs) that can drive redox reactions at their extremities. Time-lapse fluorescence imaging reveals that p- and n-doping that originated from neighboring BPEs can interact to form multiple light-emitting p-n junctions in series. This provides direct evidence of the working principle of bulk homojunction PLECs. The propagation of p-doping is faster from the BPEs than from the positive driving electrode due to electric field enhancement at the extremities of BPEs. The effect of field enhancement and the fact that the doping fronts only need to travel the distance between the neighboring BPEs to form a light-emitting junction greatly reduce the response time for electroluminescence in the region containing the BPE array. The near simultaneous formation of multiple light-emitting p-n junctions in series causes a measurable increase in cell current. This indicates that the region containing a BPE is much more conductive than the rest of the planar cell despite the latter's greater width. The p- and n-doping originating from the BPEs is initially highly confined. Significant expansion and divergence of doping occurred when the region containing the BPE array became more conductive. The shape and direction of expanded doping strongly suggest that the multiple light-emitting p-n junctions, formed between and connected by the array of metal BPEs, have functioned as a single rod-shaped BPE. This represents a new type of BPE that is formed in situ and as a combination of metal, doped polymers, and forward-biased p-n junctions connected in series.