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31.
Catherine M. Mills Thomas Z. Benton Ivett Pia Megan J. Francis Leticia Reyes Nathan G. Dolloff Yuri K. Peterson Patrick M. Woster 《Chemical science》2023,14(8):2168
High-risk neuroblastoma (NB) accounts for 15% of all pediatric cancer deaths. Refractory disease for high-risk NB patients is attributed to chemotherapy resistance and immunotherapy failure. The poor prognosis for high-risk NB patients demonstrates an unmet medical need for the development of new, more efficacious therapeutics. CD38 is an immunomodulating protein that is expressed constitutively on natural killer (NK) cells and other immune cells in the tumor microenvironment (TME). Furthermore, CD38 over expression is implicated in propagating an immunosuppressive milieu within the TME. Through virtual and physical screening, we have identified drug-like small molecule inhibitors of CD38 with low micromolar IC50 values. We have begun to explore structure activity relationships for CD38 inhibition through derivatization of our most effective hit molecule to develop a new compound with lead-like physicochemical properties and improved potency. We have demonstrated that our derivatized inhibitor, compound 2, elicits immunomodulatory effects in NK cells by increasing cell viability by 190 ± 36% in multiple donors and by significantly increasing interferon gamma. Additionally, we have illustrated that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. Herein we describe the synthesis and biological evaluation of small molecule CD38 inhibitors and demonstrate their potential utility as a novel approach to NB immunotherapy. These compounds represent the first examples of small molecules that stimulate immune function for the treatment of cancer.Small molecule inhibitors of CD38 promote increases in interferon gamma and stimulate natural killer cell proliferation for the treatment of neuroblastoma. 相似文献
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33.
Abe F Akimoto H Akopian A Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Aota S Apollinari G Asakawa T Ashmanskas W Atac M Auchincloss P Azfar F Azzi-Bacchetta P Bacchetta N Badgett W Bagdasarov S Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Berryhill J Bertolucci S Bhatti A Biery K Binkley M Bisello D Blair RE Blocker C 《Physical review letters》1996,76(12):2006-2010
34.
Abe F Akimoto H Akopian A Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Aota S Apollinari G Asakawa T Ashmanskas W Atac M Auchincloss P Azfar F Azzi-Bacchetta P Bacchetta N Badgett W Bagdasarov S Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Barzi E Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Berryhill J Bertolucci S Bhatti A Biery K Binkley M Bisello D Blair RE 《Physical review letters》1996,77(3):438-443
35.
Abe F Akimoto H Akopian A Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Aota S Apollinari G Asakawa T Ashmanskas W Atac M Azfar F Azzi-Bacchetta P Bacchetta N Badgett W Bagdasarov S Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Barzi E Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Berryhill J Bertolucci S Bhatti A Biery K Binkley M Bisello D Blair RE Blocker C Bodek A 《Physical review letters》1996,76(25):4675-4680
36.
Abe F Akimoto H Akopian A Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Aota S Apollinari G Asakawa T Ashmanskas W Atac M Azfar F Azzi-Bacchetta P Bacchetta N Badgett W Bagdasarov S Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Barzi E Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Berryhill J Bertolucci S Bevensee B Bhatti A Biery K Binkley M Bisello D Blair RE Blocker C 《Physical review D: Particles and fields》1996,54(11):6596-6609
37.
Abe F Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Apollinari G Areti H Atac M Auchincloss P Azfar F Azzi P Bacchetta N Badgett W Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Bartalini P Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Bertolucci S Bhatti A Biery K Binkley M Bird F Bisello D Blair RE Blocker C Bodek A Bokhari W Bolognesi V Bortoletto D Boswell C Boulos T 《Physical review D: Particles and fields》1996,53(3):1051-1065
38.
Abe F Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Apollinari G Areti H Atac M Auchincloss P Azfar F Azzi P Bacchetta N Badgett W Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Bartalini P Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Bertolucci S Bhatti A Biery K Binkley M Bird F Bisello D Blair RE Blocker C Bodek A Bokhari W Bolognesi V Bortoletto D Boswell C Boulos T 《Physical review D: Particles and fields》1996,53(7):3496-3505
39.
Ionizing radiation environment models, a 3-D spacecraft mass model, and radiation transport codes have been used to predict the radiation dose and linear energy transfer (LET) spectra measured at various locations on the LDEF satellite. The predictions are compared with thermoluminescent dosimeter measurements of the trapped proton and electron doses and with LET spectra measured by plastic nuclear track detectors. The predicted vs observed comparisons indicate some of the uncertainties of present ionizing radiation environment models for low Earth-orbit missions. 相似文献
40.
Abe F Albrow MG Amendolia SR Amidei D Antos J Anway-Wiese C Apollinari G Areti H Atac M Auchincloss P Azfar F Azzi P Bacchetta N Badgett W Bailey MW Bao J de Barbaro P Barbaro-Galtieri A Barnes VE Barnett BA Bartalini P Bauer G Baumann T Bedeschi F Behrends S Belforte S Bellettini G Bellinger J Benjamin D Benlloch J Bensinger J Benton D Beretvas A Berge JP Bertolucci S Bhatti A Biery K Binkley M Bird F Bisello D Blair RE Blocker C Bodek A Bokhari W Bolognesi V Bortoletto D Boswell C Boulos T 《Physical review letters》1995,75(4):608-612