| Reference | 1. Cancer Res. 2011 Jan 15;71(2):435-44. doi: 10.1158/0008-5472.CAN-10-2876. Epub
2010 Dec 1.
<br>
Small molecule inhibition of GDC-0449 refractory smoothened mutants and
downstream mechanisms of drug resistance.
<br>
Dijkgraaf GJ(1), Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D,
Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, de Sauvage
FJ.
<br>
Author information: <br>
(1)Department of Molecular Biology, Genentech Inc., South San Francisco,
California 94080, USA.
<br>
Inappropriate Hedgehog (Hh) signaling has been directly linked to medulloblastoma
(MB), a common malignant brain tumor in children. GDC-0449 is an Hh pathway
inhibitor (HPI) currently under clinical investigation as an anticancer agent.
Treatment of a MB patient with GDC-0449 initially regressed tumors, but this
individual ultimately relapsed with a D473H resistance mutation in Smoothened
(SMO), the molecular target of GDC-0449. To explore the role of the mutated
aspartic acid residue in SMO function, we substituted D473 with every amino acid
and found that all functional mutants were resistant to GDC-0449, with positively
charged residues conferring potential oncogenic properties. Alanine scan
mutagenesis of SMO further identified E518 as a novel prospective mutation site
for GDC-0449 resistance. To overcome this form of acquired resistance, we
screened a panel of chemically diverse HPIs and identified several antagonists
with potent in vitro activity against these GDC-0449-resistant SMO mutants. The
bis-amide compound 5 was of particular interest, as it was able to inhibit tumor
growth mediated by drug resistant SMO in a murine allograft model of MB. However,
focal amplifications of the Hh pathway transcription factor Gli2 and the Hh
target gene cyclin D1 (Ccnd1) were observed in two additional resistant models,
indicating that resistance may also occur downstream of SMO. Importantly, these
HPI resistant MB allografts retained their sensitivity to PI3K inhibition,
presenting additional opportunities for the treatment of such tumors.
<br>
2. Expert Opin Investig Drugs. 2010 Mar;19(3):451-4. doi: 10.1517/13543780903571649.
<br>
The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other
cancers.
<br>
Doggrell SA(1).
<br>
Author information: <br>
(1)Queensland University of Technology, School of Life Sciences, Faculty of
Science and Technology, GPO Box 2434, QLD4001, Brisbane, Australia.
[email protected]
<br>
BACKGROUND: The hedgehog signalling pathway is vital in early development, but
then becomes dormant, except in some cancer tumours. Hedgehog inhibitors are
being developed for potential use in cancer.<br>
OBJECTIVES/METHODS: The objective of this evaluation is to review the initial
clinical studies of the hedgehog inhibitor, GDC-0449, in subjects with cancer.
RESULTS: Phase I trials have shown that GDC-0449 has benefits in subjects with
metastatic or locally advanced basal-cell carcinoma and in one subject with
medulloblastoma. GDC-0449 was well tolerated.<br>
CONCLUSIONS: Long-term efficacy and safety studies of GDC-0449 in these
conditions and other solid cancers are now underway. These clinical trials with
GDC-0449, and trials with other hedgehog inhibitors, will reveal whether it is
beneficial and safe to inhibit the hedgehog pathway in a wide range of solid
tumours or not.
<br>
3. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5576-81. doi: 10.1016/j.bmcl.2009.08.049.
Epub 2009 Aug 15.
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GDC-0449-a potent inhibitor of the hedgehog pathway.
<br>
Robarge KD(1), Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE,
Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MF, Kotkow K, La
H, Lalonde RL, Lau K, Lee L, Marshall D, Marsters JC Jr, Murray LJ, Qian C, Rubin
LL, Salphati L, Stanley MS, Stibbard JH, Sutherlin DP, Ubhayaker S, Wang S, Wong
S, Xie M.
<br>
Author information: <br>
(1)Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA
94080, United States. [email protected]
<br>
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to
the discovery of functionalized 2-pyridyl amides as novel inhibitors of the
hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and
drug-like properties by modifications to the amide portion of the molecule
resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses
as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly
dependent on the Hh pathway for growth and is currently in human clinical trials,
where it is initially being evaluated for the treatment of BCC.
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