0 6 Potent potent JJ 7 11 gene gene NN 12 22 regulatory regulatory JJ 23 26 and and CC 27 44 antiproliferative antiproliferative JJ 45 55 activities activity NNS 56 58 of of IN 59 68 20-methyl 20-methyl NN 69 78 analogues analogue NNS 79 81 of of IN 82 86 1,25 1,25 CD 87 103 dihydroxyvitamin dihydroxyvitamin NN 104 106 D3 d3 NN 106 107 . . . 109 112 The the DT 113 123 biological biological JJ 124 130 active active JJ 131 135 form form NN 136 138 of of IN 139 146 vitamin vitamin NN 147 149 D3 d3 NN 149 150 , , , 151 172 1,25-dihydroxyvitamin 1,25-dihydroxyvitamin NN 173 175 D3 D3 NNP 176 177 ( ( ( 177 179 VD VD NNP 179 180 ) ) ) 180 181 , , , 182 191 regulates regulate VBZ 192 200 cellular cellular JJ 201 207 growth growth NN 208 211 and and CC 212 227 differentiation differentiation NN 227 228 . . . 229 233 This this DT 234 242 provides provide VBZ 243 246 the the DT 247 254 hormone hormone NN 255 259 with with IN 260 262 an an DT 263 274 interesting interesting JJ 275 286 therapeutic therapeutic JJ 287 296 potential potential NN 296 297 . . . 298 305 However however RB 305 306 , , , 307 320 hypercalcemia hypercalcemia NN 321 323 is be VBZ 324 325 a a DT 326 330 side side NN 331 337 effect effect NN 337 338 , , , 339 344 which which WDT 345 347 is be VBZ 348 354 caused cause VBN 355 357 by by IN 358 360 VD VD NNP 360 362 ’s 's POS 363 372 classical classical JJ 373 379 action action NN 379 380 , , , 381 384 the the DT 385 395 regulation regulation NN 396 398 of of IN 399 406 calcium calcium NN 407 418 homeostasis homeostasis NN 418 419 . . . 420 424 This this DT 425 429 made make VBD 430 433 the the DT 434 438 need need NN 439 442 for for IN 443 445 VD vd NN 446 455 analogues analogue NNS 456 460 with with IN 461 472 selectively selectively RB 473 482 increased increase VBN 483 487 cell cell NN 488 498 regulatory regulatory JJ 499 509 properties property NNS 509 510 . . . 511 518 Studies study NNS 519 523 with with IN 524 530 20-epi 20-epi JJ 531 540 analogues analogue NNS 541 548 pointed point VBD 549 552 out out RP 553 556 the the DT 557 567 importance importance NN 568 570 of of IN 571 574 the the DT 575 584 carbon-20 carbon-20 NN 585 593 position position NN 594 597 and and CC 598 601 led lead VBD 602 604 to to TO 605 608 the the DT 609 620 development development NN 621 623 of of IN 624 633 20-methyl 20-methyl NN 634 645 derivatives derivative NNS 646 648 of of IN 649 651 VD VD NNP 651 652 . . . 653 655 In in IN 656 660 this this DT 661 667 report report NN 668 671 the the DT 672 682 biological biological JJ 683 693 properties property NNS 694 696 of of IN 697 700 the the DT 701 710 compounds compound NNS 711 719 ZK161422 zk161422 NN 720 723 and and CC 724 732 ZK157202 zk157202 NN 732 733 , , , 734 739 which which WDT 740 743 are be VBP 744 754 20-methyl- 20-methyl- JJ 755 758 and and CC 759 784 20-methyl-23-eneanalogues 20-methyl-23-eneanalogue NNS 784 785 , , , 786 798 respectively respectively RB 798 799 , , , 800 804 have have VBP 805 809 been be VBN 810 818 analyzed analyze VBN 819 821 in in IN 822 832 comparison comparison NN 833 837 with with IN 838 840 VD VD NNP 840 841 . . . 842 846 Both both DT 847 856 compounds compound NNS 857 861 show show VBP 862 867 about about IN 868 874 2-fold 2-fold RB 875 880 lower low JJR 881 889 affinity affinity NN 890 892 to to TO 893 896 the the DT 897 899 VD VD NNP 900 908 receptor receptor NN 909 910 ( ( ( 910 913 VDR VDR NNP 913 914 ) ) ) 915 919 than than IN 920 922 VD VD NNP 922 923 . . . 924 931 However however RB 931 932 , , , 933 941 compared compare VBN 942 944 to to TO 945 947 VD VD NNP 947 948 , , , 949 954 their their PRP$ 955 972 antiproliferative antiproliferative JJ 973 979 effect effect NN 980 982 is be VBZ 983 985 up up IN 986 988 to to TO 989 996 30-fold 30-fold RB 997 1003 higher high JJR 1004 1006 on on IN 1007 1012 human human JJ 1013 1023 peripheral peripheral JJ 1024 1029 blood blood NN 1030 1041 mononuclear mononuclear JJ 1042 1047 cells cell NNS 1048 1051 and and CC 1052 1056 even even RB 1057 1059 up up RB 1060 1062 to to TO 1063 1071 300-fold 300-fold RB 1072 1078 higher high JJR 1079 1081 on on IN 1082 1087 human human JJ 1088 1094 breast breast NN 1095 1101 cancer cancer NN 1102 1107 MCF-7 mcf-7 NN 1108 1113 cells cell NNS 1113 1114 . . . 1115 1122 Whereas whereas IN 1123 1126 the the DT 1127 1140 hypercalcemic hypercalcemic JJ 1141 1147 effect effect NN 1148 1151 for for IN 1152 1160 ZK157202 zk157202 NN 1161 1163 is be VBZ 1164 1168 also also RB 1169 1178 increased increase VBN 1179 1186 10-fold 10-fold RB 1186 1187 , , , 1188 1196 ZK161422 ZK161422 NNP 1197 1200 has have VBZ 1201 1204 the the DT 1205 1209 same same JJ 1210 1228 calcium-mobilizing calcium-mobilizing JJ 1229 1236 potency potency NN 1237 1239 as as IN 1240 1242 VD VD NNP 1242 1243 . . . 1244 1252 Moreover moreover RB 1252 1253 , , , 1254 1262 ZK161422 ZK161422 NNP 1262 1263 , , , 1264 1267 but but CC 1268 1271 not not RB 1272 1280 ZK157202 zk157202 NN 1280 1281 , , , 1282 1288 showed show VBD 1289 1299 preference preference NN 1300 1303 for for IN 1304 1308 gene gene NN 1309 1319 activation activation NN 1320 1324 from from IN 1325 1326 a a DT 1327 1335 promoter promoter NN 1336 1344 carrying carry VBG 1345 1346 a a DT 1347 1349 VD VD NNP 1350 1358 response response NN 1359 1366 element element NN 1367 1371 with with IN 1372 1373 a a DT 1374 1385 palindromic palindromic JJ 1386 1397 arrangement arrangement NN 1398 1400 of of IN 1401 1404 two two CD 1405 1414 hexameric hexameric JJ 1415 1423 receptor receptor NN 1424 1431 binding binding NN 1432 1437 sites site NNS 1438 1444 spaced space VBN 1445 1447 by by IN 1448 1449 9 9 CD 1450 1461 nucleotides nucleotide NNS 1462 1463 ( ( ( 1463 1466 IP9 IP9 NNP 1466 1467 ) ) ) 1468 1474 rather rather RB 1475 1479 than than IN 1480 1483 for for IN 1484 1494 activation activation NN 1495 1499 from from IN 1500 1501 a a DT 1502 1510 response response NN 1511 1518 element element NN 1519 1525 formed form VBN 1526 1528 by by IN 1529 1530 a a DT 1531 1537 direct direct JJ 1538 1544 repeat repeat NN 1545 1551 spaced space VBN 1552 1554 by by IN 1555 1556 3 3 CD 1557 1568 nucleotides nucleotide NNS 1569 1570 ( ( ( 1570 1573 DR3 DR3 NNP 1573 1574 ) ) ) 1574 1575 . . . 1576 1580 This this DT 1581 1592 observation observation NN 1593 1601 supports support VBZ 1602 1603 a a DT 1604 1609 model model NN 1609 1610 , , , 1611 1613 in in IN 1614 1619 which which WDT 1620 1628 promoter promoter NN 1629 1640 selectivity selectivity NN 1641 1649 reflects reflect VBZ 1650 1653 the the DT 1654 1665 selectively selectively RB 1666 1675 increased increase VBN 1676 1693 antiproliferative antiproliferative JJ 1694 1700 effect effect NN 1701 1703 of of IN 1704 1706 VD vd NN 1707 1716 analogues analogue NNS 1716 1717 . . .