| IUPAC Name | (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(2R)-1-[(1S,3R,4R)-4-dimethylphosphoryloxy-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone |
| InChI | InChI=1S/C53H84NO14P/c1-32-18-14-13-15-19-33(2)44(63-8)30-40-23-21-38(7)53(61,67-40)50(58)51(59)54-25-17-16-20-41(54)52(60)66-45(35(4)28-39-22-24-43(46(29-39)64-9)68-69(11,12)62)31-42(55)34(3)27-37(6)48(57)49(65-10)47(56)36(5)26-32/h13-15,18-19,27,32,34-36,38-41,43-46,48-49,57,61H,16-17,20-26,28-31H2,1-12H3/b15-13+,18-14+,33-19+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 |
| Reference | 1. Expert Opin Investig Drugs. 2008 Dec;17(12):1947-54. doi:
10.1517/13543780802556485 .
<br>
Deforolimus (AP23573) a novel mTOR inhibitor in clinical development.
<br>
Mita M(1), Sankhala K, Abdel-Karim I, Mita A, Giles F.
<br>
Author information: <br>
(1)Institute for Drug Development, Cancer Therapy and Research Center, UT Health
Science Center, San Antonio, USA. [email protected]
<br>
mTOR was determined to be a promising anticancer target and several drug
inhibitors of mTOR are currently in clinical development. Rapamycin (RAP) was the
first mTOR inhibitor discovered. However, RAP has poor aqueous solubility and
chemical stability and therefore its utilization at doses susceptible to produce
an effect as an anticancer agent is limited. This represented the main rationale
for developing new RAP analogs. The RAP analogs currently in clinical development
as anticancer agents include temsirolimus (CCI-779), everolimus (RAD-001), and
deforolimus (AP23573). These agents have demonstrated antiproliferative activity
against a diverse range of malignancies in preclinical studies, and clinical
evaluations have been very encouraging thus far. Deforolimus (AP23573), a non-RAP
prodrug, has been tested in Phase I and II clinical trials and shows promising
results in several tumor types including sarcoma. A Phase III study in patients
with sarcoma is currently ongoing. The preclinical and clinical studies with
deforolimus will be presented.
<br>
2. Clin Cancer Res. 2008 May 1;14(9):2756-62. doi: 10.1158/1078-0432.CCR-07-1372.
<br>
A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian
target of rapamycin inhibitor, in patients with relapsed or refractory
hematologic malignancies.
<br>
Rizzieri DA(1), Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, Rivera VM,
Albitar M, Bedrosian CL, Giles FJ.
<br>
Author information: <br>
(1)Duke University Medical Center, Durham, North Carolina 27710, USA.
[email protected]
<br>
PURPOSE: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits
the mammalian target of rapamycin, a downstream effector of the
phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial
was conducted to determine the efficacy and safety of single-agent deforolimus in
patients with relapsed or refractory hematologic malignancies.<br>
EXPERIMENTAL DESIGN: Eligible patients were assigned to one of five
disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute
infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used
for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor
response were assessed.<br>
RESULTS: Fifty-five patients received deforolimus as follows: cohort 1 23 acute
myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous
leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia;
cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic
leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma.
Most patients were heavily pretreated. Of the 52 evaluable patients, partial
responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and
three of nine mantle cell lymphoma. Hematologic improvement/stable disease was
observed in 21 (40%). Common treatment-related adverse events, which were
generally mild and reversible, were mouth sores, fatigue, nausea, and
thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute
myelogenous leukemia/myelodysplastic syndrome patients after therapy showed
mammalian target of rapamycin inhibition by deforolimus.<br>
CONCLUSIONS: Deforolimus was well-tolerated in patients with heavily pretreated
hematologic malignancies, and antitumor activity was observed. Further
investigation of deforolimus alone and in combination with other therapeutic
agents is warranted in patients with selected hematologic malignancies.
<br>
3. J Clin Oncol. 2008 Jan 20;26(3):361-7. doi: 10.1200/JCO.2007.12.0345.
<br>
Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus
(AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to
patients with advanced malignancies.
<br>
Mita MM(1), Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A,
Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL,
Tolcher AW.
<br>
Author information: <br>
(1)Cancer Therapy and Research Center, Institute for Drug Development, The
University of Texas Health Science Center, San Antonio, TX, USA.
<br>
PURPOSE: This phase I trial was conducted to determine the safety, tolerability,
pharmacokinetics, and pharmacodynamics of deforolimus (previously known as
AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid
malignancies.<br>
PATIENTS AND METHODS: Patients were treated using an accelerated titration design
with sequential escalating flat doses of deforolimus administered as a 30-minute
intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a
28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response
assessments were performed.<br>
RESULTS: Thirty-two patients received at least one dose of deforolimus (3 to 28
mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported.
The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse
events included reversible mouth sores and rash. Whole-blood clearance increased
with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin
inhibition at all dose levels. Four patients (one each with non-small-cell lung
cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing
sarcoma) experienced confirmed partial responses, and three additional patients
had minor tumor regressions.<br>
CONCLUSION: The MTD of this phase I trial using an accelerated titration design
was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed
encouraging antitumor activity across a broad range of malignancies when
administered intravenously on the QDx5 schedule. On the basis of these overall
results, a dose of 12.5 mg/d is being evaluated in phase II trials.
<br>
|
