TECHNOLOGY BACKGROUND
Tumors of the prostate, breast and
endometrirum are hormone dependent and standard treatment of care often uses
hormone ablative therapies. These therapies can include inhibitors of steroid
hormone biosynthesis e.g. aromatase inhibitors (for breast cancer), 5a-reductase inhibitors (for prostate
cancer), and steroid receptor antagonists e.g. tamoxifen (for breast cancer)
and bicalutamide (for prostate cancer). While these agents are widely used,
they block the action of estrogens and androgens non-specifically and have untoward
side effects. In addition, resistance develops to these agents. The Penzymes team
has recognized that enzymes that belong to the aldo-keto reductase (AKR) superfamily
are required for hormone synthesis in a tumor specific manner creating the
concept that it is possible to block steroid hormone synthesis within these
tumors with precision.
SIMS FOR CASTRATION RESISTANT PROSTATE CANCER (CRPC)
Dr. Penning’s team has identified
AKR1C3 (17b-hydroxysteroid dehydrogenase type 5)
as a unique target in CRPC. All pathways to the most potent androgen 5a-dihydrotestosterone proceed through
AKR1C3. AKR1C3 is highly over expressed in CRPC and it is up-regulated upon
androgen deprivation, in cell lines, in tumor xenografts, and in metastatic
tissues in prostate cancer patients. Genetic manipulation (knock down
approaches) and pharmacological inhibition shows that AKR1C3 is necessary and
sufficient to drive androgen dependent gene expression and cell proliferation.
Recent work has identified
nonsteroidal anti-inflammatory drugs (NSAIDs) as potent but non-specific
inhibitors of AKR1C3, providing a framework for discovering more specific
inhibitors of AKR1C3. To this end three different classes of SIMs are in development
as lead therapeutic agents [Class 1] N-phenylaminobenzoates; [Class 2] Naphthylaminobenzoates; and [Class 3]
indomethacin analogs. Compounds in all three classes: have nanomolar potency for AKR1C3 in in vitro assays; are selective and do not inhibit any of the
other nine human AKRs; they do not inhibit the NSAID targets COX-1 and COX-2; they block testosterone biosynthesis in
prostate cancer cell lines that over express AKR1C3; and they block androgen
dependent gene expression e.g. PSA. Compounds in Class 2 have the unexpected
property of acting as AKR1C3 inhibitors and as androgen receptor antagonists
making them bifunctional. Bifunctional agents have the potential to be superior
to giving abiraterone and enzalutamide in combination. Patent applications have
been filed on all of the lead molecules.
|