John, I'll use the retinoids as an example of how LGND's technology
works. The retinoids are particularly useful because there has
been more work done here, but all of the non-polypeptide hormone
receptors are structurally similar, so what applies to one set will
probably apply to all. LGND and AGN formed a joint venture to
focus on retinoids. AGN focuses on skin and eye diseases and LGND
targets cancer and previous retinoids had shown promise in both areas.
The Medicinal chemist had a large library of retinoids. I think
LGND has now screened 2400 compounds. There were two sets of
three closely related receptors. Three RARs (Retinoic Acid Receptors)
has been isolated (alph, beta, and gamma). The commercial ligand
was tretinoin. JNJ had used it as the active ingredient in Retin-A.
Tretinoin is an all trans retinoid. Its complications included skin
irratation and a short biologocal half life because it induces its
own metabolism. Thus, there were problems with use for chronic
diseases such as cancer. The compund causes cells to differentiate
(become more specialized) which is a positive for treating cancer
because many cancers are due to de-differentiation (the cell stops
doing a specific function and instead spends most of its energy just
dividing). Subsequently JNJ produced a second formulation for
treating wrinkles. The new compound is Renova. Roche also use
tretinoin as the active ingredient in its oral (pill) formulation, Vessanoid,
for treating cancer (Acute Promyelocytic Leukemia). Roche use
a derivative, isotretinoin, as the active ingredient in Accutane.
LGND consultant, Ron Evans, discovered a new polypeptide hormone,
9-cis retinoic acid, the first non-polypeptide hormone discovered in
25 years. It bound to RARs, but also bound to a new class of related
receptors, called RXRs (alpha, beta, and gamma). Binding of hormone
to the new receptors induces apoptosis, programmed cell death.
This is the natural way the organism rids itself of unwanted cells
and again has obvious applications for cancer (adding the hormone
convinces the cancer cell to self destruct). 9-cis retinoic acid was
also called ALRT1057 or Panretin (because it binds to all six receptors).
Targretin is another analog that is specific for RXRs (binds to
the three receptors that induce apoptosis). The screening was
so successful that LGND formed another company, Allergan Ligand
Retinoid Therapeutics. This company (ALRIZ) only has one employee,
but began with a $100 million bank account to fund retinoid R&D.
In addition to Targretin (which is owned by LGND), there have been
8 additional compounds named by ALRIZ (7 in their annual report and
an eighth compound described in the literature). These compounds
are agonists. However, there is another group that act as antagonists
and they were mentioned as a group in the annual report, but mentioned
for a specific application (to treat some of the problems asociated with
the above commercial compounds) at H&Q.
Recently, use of Targretin to prevent breast cancer and treat type II
diabetes was described. The compound also appears interact with
PPARs which are other receptors activated by the wonder drugs in the TZD
class (for treating type II diabetes).
More later.
Henry |
