|
Molecular structures of geldanamycin and its
analogs, 17-AAG and 17-DMAG.
|
Geldanamycin (NSC 122750)
17-AAG (NSC 330507)
17-DMAG (NSC 707545)
1968 Heat shock protein
90 (Hsp90) is an abundant molecular chaperone that plays a major role
in the folding and activation of several signaling proteins that promote
the growth and survival of tumor cells. Geldanamycin, originally submitted
by the Upjohn Company, induces the degradation of these signaling proteins
and, consequently, the death of the malignant cells. Although geldanamycin
was active in preclinical studies, it was a poor candidate for clinical
trials due to its in vivo toxicity and instability.
1980 DTP has worked
on several geldanamycin derivatives in an effort to develop nontoxic,
more readily soluble analogs of the drug.
1992 17-allylamino
demethoxygeldanamycin (17-AAG) is an analog of geldanamycin. This drug
has been undergoing phase I/II clinical trials since 1999. 17-AAG is an
ansamycin derivative that binds specifically to Hsp90 in a manner similar
to that of geldanamycin itself. 17-AAG also leads to degradation of several
Hsp90-induced signaling proteins. Even though Hsp90 binding by 17-AAG
is weaker than binding by geldanamycin, 17-AAG and geldanamycin cause
biologic effects in tumor cells at similar doses. Since 17-AAG has a better
toxicity profile than geldanamycin, it is clearly a more engaging clinical
candidate. Preliminary results indicate that the target dose of this analog
can be achieved without dose-limiting toxicity.
1997–1998 17-dimethylaminoethylamino
demethoxygeldanamycin hydrochloride (17-DMAG), another geldanamycin analog,
has excellent bioavailability, is widely distributed to tissues, and is
quantitatively metabolized much less than is 17-AAG.1
2002–2004 17-DMAG
is being studied for treating patients with solid tumors or lymphomas.2
Link:
17-AAG poster
(pdf)
|
Although
17-AAG and 17-DMAG both exhibit activity in numerous tumor models, only
17-DMAG is active when given orally.
|
