2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

pound. 14 This chemical probe, PI-103, exhibited advantages
over wortmannin and LY294002, with excellent potency and
selectivity for class I PI3 kinases compared with a panel of
other protein and lipid kinases. PI-103 exhibited therapeutic
activity against human tumor xenograft models representing
various cancer types, including several with PIK3CA
mutations or loss of PTEN, which are predicted to be
“addicted” to the PI3 kinase pathway. 15 The antitumor
activity of PI-103 was also associated with effects on pharmacodynamic
pathway biomarkers, including reduced phosphorylation
of downstream substrates such as AKT,
providing evidence of target engagement. The biomarker
results were fully consistent with the therapeutic mechanism
being PI3 kinase inhibition, and, importantly, clearly
demonstrating proof-of-concept for targeting this pathway.
At the same time, it was also recognized that PI-103 had
some liabilities, specifically limited aqueous solubility and
extensive metabolism, which were considered serious drawbacks
in terms of its drug-like properties and thus its
suitability for clinical development
Subsequently, a large number of chemical analogs from
two chemical starting points—the pyridofuropyrimidines
exemplified by PI-103 and the thienopyrimidine ‘compound
12’—were designed, synthesized, and tested in an iterative
fashion. 14,16 These integrated medicinal chemistry, and
biogical evaluation efforts identified the more advanced
thienopyrimidine lead compounds, PI-540 and PI-620, which
retained the potency and selectivity of PI-103 but with much
improved aqueous solubility and reduced in vitro metabolism.
17 Although the improved absorbtion, distribution, metabolism,
and excretion properties of these compounds
resulted in correspondingly greater antitumor activity as
compared with PI-103, in vivo metabolism caused by conjugation
of a phenolic hydroxyl group remained an obstacle
to the clinical development of this series. 17 Indazoles were
investigated as replacements for the problematic phenolic
hydroxyl, with the intention that they might markedly
reduce metabolism while maintaining the necessary target
interaction with PI3 kinase, as revealed by protein-ligand
X-ray cocrystal structures (Fig. 2). This strategy paid off and
GDC-0941 (PI-728) was identified as a potent and selective
KEY POINTS
● The PI3K pathway is frequently activated by oncogenic
mutations in many different cancers.
● Inhibiting the PI3K pathway is an attractive approach
to exploit the resulting oncogenic addictions
and vulnerabilities.
● A number of potent and selective PI3K inhibitors
have been discovered and are now in clinical studies.
● Although fit-for-purpose target engagement biomarkers
are now available, identifying predictive biomarkers
for patient stratification remains a major
challenge; current “predictive” biomarkers are useful
for enrichment of early clinical trials with patients
more likely to respond.
● Other key challenges being addressed in the clinic are
to define optimal PI3 kinase selectivity profiles and to
explore rational drug combinations.
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WORKMAN AND CLARKE
inhibitor pan-class I PI3 kinase inhibitor with excellent
drug-like properties, including good oral bioavailability, a
major advantage over the previous analogs. 18 Interestingly,
GDC-0941 retained full therapeutic activity, at least in the
cancer models tested, despite lacking mTOR inhibition,
which was in contrast to previous analogs such as PI-103. 17
A subsequent structurally related clinical candidate GDC-
0980 does inhibit mTOR, providing an interesting comparator.
19
The improved pharmacokinetic profile of GDC-0941 resulted
in profound and prolonged target engagement, demonstrated
by inhibition of PI3 kinase pathway biomarkers in
human cancer xenografts, consistent with the sustained
tumor drug exposure (Fig. 3). In these experiments, tumor
drug levels were well above antiproliferative GI 50 concentrations
for at least 6 hours, and decreased phosphorylation
of AKT together with other pathway markers was maintained
for at least 8 hours (Fig. 3). 17
As a result of these enhanced pharmacokinetic and pharmacodynamic
properties, GDC-0941 exhibited excellent
dose-dependent therapeutic activity in the PTEN null, PI3
kinase pathway-addicted U87MG human glioblastoma
xenograft model (Fig. 3). Activity was also demonstrated in
another “PI3 kinase-addicted” tumor, the IGROV-1 ovarian
cancer carrying both an activating PIK3CA mutation and
lacking PTEN expression and also in additional human
tumor xenografts. 17,20
The linkage of pharmacokinetic exposure, biomarker
changes in the PI3 kinase pathway, and therapeutic tumor
response provided a convincing pharmacologic audit trail
(PhaT 21 ) for GDC-0941, which formed a solid platform for
subsequent clinical studies. On the basis of its very attractive
molecular, pharmacologic, and therapeutic profile, together
with its excellent selectivity profile for class I PI3
kinase compared with a wide range of other kinases, GDC-
0941 was selected for clinical development. As mentioned
earlier, there are now a considerable number of PI3 kinase
inhibitors undergoing clinical trials and still more in preclinical
discovery and development. 10
Current Challenges and Future Opportunities
It is important to assess the critical challenges that we
face in the development of PI3 kinase inhibitors for cancer
treatment. 22 A major question is certainly the desired specificity
toward the various individual PI3 kinase family
members. There has been some real progress, particularly in
designing and evaluating inhibitors with different isoform
selectivities, often facilitated by structure-based design (Fig.
2). However, the definition of the optimal PI3 kinase isoform
selectivity profile or profiles—which may well depend on
tumor genetics—is still a major ongoing research activity.
For example, we remain unsure about whether the addition
of mTOR inhibitory activity to a class I PI3 kinase inhibitor
activity is advantageous, e.g., for overcoming feedback loops.
In addition, it is also not yet clearly established whether
individual compared with combinatorial inhibition of class I
isoforms is advantageous—especially given that most clinical
candidates inhibit all 4 class I isoforms with low nanomolar
potency and appear to be generally well tolerated,
at least in the short to medium term. The preferred profiles
will emerge with time from clinical experience coupled with
mechanistic preclinical studies.
The issue of biomarkers is a critically important one. The