0 3 Two two CD 4 18 glucocorticoid glucocorticoid NN 19 26 binding binding NN 27 32 sites site NNS 33 35 on on IN 36 39 the the DT 40 45 human human JJ 46 60 glucocorticoid glucocorticoid NN 61 69 receptor receptor NN 69 70 . . . 72 87 Glucocorticoids glucocorticoid NNS 88 91 are be VBP 92 97 known know VBN 98 100 to to TO 101 105 have have VB 106 107 a a DT 108 113 lytic lytic JJ 114 120 effect effect NN 121 123 in in IN 124 132 leukemic leukemic JJ 133 138 cells cell NNS 139 142 via via IN 143 155 interactions interaction NNS 156 160 with with IN 161 164 the the DT 165 179 glucocorticoid glucocorticoid NN 180 188 receptor receptor NN 189 190 ( ( ( 190 192 GR GR NNP 192 193 ) ) ) 193 194 . . . 195 203 Cortisol Cortisol NNP 204 207 and and CC 208 215 various various JJ 216 225 synthetic synthetic JJ 226 241 glucocorticoids glucocorticoid NNS 242 246 bind bind VBP 247 249 to to TO 250 253 the the DT 254 256 GR gr NN 257 261 with with IN 262 270 one-site one-site JJ 271 279 kinetics kinetic NNS 279 280 . . . 281 291 Cortivazol Cortivazol NNP 292 293 ( ( ( 293 296 CVZ CVZ NNP 296 297 ) ) ) 298 300 is be VBZ 301 302 a a DT 303 309 unique unique JJ 309 310 , , , 311 315 high high JJ 316 323 potency potency NN 324 333 synthetic synthetic JJ 334 348 glucocorticoid glucocorticoid NN 348 349 , , , 350 355 which which WDT 356 359 has have VBZ 360 361 a a DT 362 375 phenylpyrazol phenylpyrazol NN 376 381 fused fuse VBN 382 384 to to TO 385 388 the the DT 389 395 A-ring a-ring NN 396 398 of of IN 399 402 the the DT 403 410 steroid steroid NN 411 418 nucleus nucleus NN 419 422 and and CC 423 431 displays display VBZ 432 439 binding binding NN 440 450 consistent consistent JJ 451 455 with with IN 456 459 two two CD 460 462 or or CC 463 467 more more JJR 468 473 sites site NNS 474 476 in in IN 477 480 the the DT 481 488 cytosol cytosol NN 489 493 from from IN 494 497 CEM CEM NNP 498 500 C7 c7 NN 501 506 cells cell NNS 507 508 ( ( ( 508 509 a a DT 510 515 human human JJ 516 521 acute acute JJ 522 535 lymphoblastic lymphoblastic JJ 536 542 T-cell t-cell NN 543 547 line line NN 547 548 ) ) ) 548 549 . . . 550 552 It it PRP 553 556 has have VBZ 557 567 previously previously RB 568 572 been be VBN 573 578 shown show VBN 579 583 that that IN 584 587 the the DT 588 593 lower low JJR 594 602 affinity affinity NN 603 608 class class NN 609 611 of of IN 612 617 sites site NNS 618 621 are be VBP 622 629 similar similar JJ 630 632 in in IN 633 641 affinity affinity NN 642 645 and and CC 646 650 site site NN 651 659 molarity molarity NN 660 662 to to TO 663 668 those those DT 669 679 recognized recognize VBN 680 682 by by IN 683 696 dexamethasone dexamethasone NN 696 697 . . . 698 701 The the DT 702 708 higher high JJR 709 717 affinity affinity NN 718 723 sites site NNS 724 728 bind bind VBP 729 732 CVZ CVZ NNP 733 737 with with IN 738 741 20- 20- CD 742 744 to to TO 745 752 50-fold 50-fold JJ 753 760 greater great JJR 761 769 affinity affinity NN 769 770 , , , 771 781 consistent consistent JJ 782 786 with with IN 787 790 CVZ CVZ NNP 790 792 ’s 's POS 793 801 enhanced enhance VBN 802 812 biological biological JJ 813 820 effects effect NNS 820 821 . . . 822 824 In in IN 825 831 mutant mutant JJ 832 840 leukemic leukemic JJ 841 846 cells cell NNS 847 856 resistant resistant JJ 857 859 to to TO 860 863 the the DT 864 869 lytic lytic JJ 870 877 effects effect NNS 878 880 of of IN 881 894 dexamethasone dexamethasone NN 894 895 , , , 896 899 CVZ CVZ NNP 900 904 both both DT 905 910 lyses lysis NNS 911 914 the the DT 915 920 cells cell NNS 921 924 and and CC 925 935 recognizes recognize VBZ 936 937 a a DT 938 944 single single JJ 945 950 class class NN 951 953 of of IN 954 959 sites site NNS 960 967 similar similar JJ 968 970 to to TO 971 974 the the DT 975 979 high high JJ 980 988 affinity affinity NN 989 993 site site NN 994 996 in in IN 997 1000 CEM CEM NNP 1001 1003 C7 C7 NNP 1004 1009 cells cell NNS 1009 1010 . . . 1011 1013 We we PRP 1014 1018 have have VBP 1019 1026 carried carry VBN 1027 1030 out out RP 1031 1042 experiments experiment NNS 1043 1045 to to TO 1046 1052 define define VB 1053 1056 the the DT 1057 1063 nature nature NN 1064 1066 of of IN 1067 1070 the the DT 1071 1077 higher high JJR 1078 1086 affinity affinity NN 1087 1090 CVZ CVZ NNP 1091 1098 binding binding NN 1099 1103 site site NN 1103 1104 . . . 1105 1107 We we PRP 1108 1111 now now RB 1112 1116 show show VBP 1117 1121 that that IN 1121 1122 : : : 1123 1124 1 1 LS 1124 1125 ) ) ) 1126 1129 CVZ CVZ NNP 1130 1133 has have VBZ 1134 1138 more more JJR 1139 1143 than than IN 1144 1147 one one CD 1148 1155 binding binding NN 1156 1160 site site NN 1161 1163 in in IN 1164 1165 a a DT 1166 1172 second second JJ 1172 1173 , , , 1174 1185 independent independent JJ 1185 1186 , , , 1187 1193 B-cell b-cell NN 1194 1198 line line NN 1198 1199 , , , 1200 1204 IM-9 IM-9 NNP 1204 1205 ; ; : 1206 1207 2 2 LS 1207 1208 ) ) ) 1209 1212 the the DT 1213 1231 antiglucocorticoid antiglucocorticoid JJ 1232 1234 RU RU NNP 1235 1240 38486 38486 CD 1241 1243 is be VBZ 1244 1248 able able JJ 1249 1251 to to TO 1252 1257 block block VB 1258 1262 both both DT 1263 1266 CVZ CVZ NNP 1266 1268 ’s 's POS 1269 1275 higher high JJR 1276 1279 and and CC 1280 1285 lower low JJR 1286 1294 affinity affinity NN 1295 1300 sites site NNS 1300 1301 ; ; : 1302 1303 3 3 LS 1303 1304 ) ) ) 1305 1308 all all DT 1309 1311 of of IN 1312 1315 CVZ CVZ NNP 1315 1317 ’s 's POS 1318 1325 binding bind VBG 1326 1331 sites site NNS 1332 1335 are be VBP 1336 1338 on on IN 1339 1340 a a DT 1341 1348 protein protein NN 1349 1364 immunologically immunologically RB 1365 1382 indistinguishable indistinguishable JJ 1383 1387 from from IN 1388 1391 the the DT 1392 1397 human human JJ 1398 1400 GR gr NN 1400 1401 ; ; : 1402 1405 and and CC 1406 1407 4 4 LS 1407 1408 ) ) ) 1409 1416 freshly freshly RB 1417 1425 isolated isolate VBN 1426 1432 clones clone NNS 1433 1435 of of IN 1436 1449 CVZ-resistant cvz-resistant JJ 1450 1455 cells cell NNS 1456 1460 have have VBP 1461 1465 lost lose VBN 1466 1469 all all DT 1470 1477 binding bind VBG 1478 1483 sites site NNS 1484 1487 for for IN 1488 1491 CVZ CVZ NNP 1491 1492 . . . 1493 1498 These these DT 1499 1503 data datum NNS 1504 1512 indicate indicate VBP 1513 1517 that that IN 1518 1521 CVZ CVZ NNP 1522 1524 is be VBZ 1525 1536 recognizing recognize VBG 1537 1540 two two CD 1541 1555 glucocorticoid glucocorticoid NN 1556 1563 binding binding NN 1564 1569 sites site NNS 1570 1572 on on IN 1573 1576 the the DT 1577 1582 human human JJ 1583 1585 GR gr NN 1586 1588 or or CC 1589 1590 a a DT 1591 1598 protein protein NN 1599 1603 very very RB 1604 1611 similar similar JJ 1612 1614 to to TO 1615 1617 it it PRP 1617 1618 . . .