Curis Hedgehog and Beyond --plus multi-targeting cancer inhibitors

All of the following compounds work at blocking the activating forms of a Hh signaling protein called "SMO." IP-926 team took a well known inhibitor and made it work better. GDC-0449 said I know I want to inhibit SMO lets make a brand new inhibitor (or class of molecules). Itraconazole was found during a Stanford screen and has been in use for the last 25 years for fungal infections.

--IP-926 synthetic derivative of Cyclopamine ...

Very interesting article and is a very different approach compared to GDC-0449

LDE225 (Hedgehog inhibitor)

• Cream Form
• CONS: May not take help Odontogenic keratocyst and Plantar Pits in these patients. Will not prevent new BCCs (Unless they take the cream lotion on a regular basis)
• PROS: Min/No side effects. No hair loss or muscle spasms

GDC-0449 (Hedgehog inhibitor)

• Systemic
• CONS: Higher incidence side effects.
• PROS: Will probably prevent new BCCs for forming. Will ...

Abstract
BACKGROUND: Odontogenic keratocysts of the jaw are a central feature of basal cell nevus syndrome (BCNS) and arise from the basal cell layer of the surface epithelium. Although they are benign, they tend to be aggressive, with local invasion of bony structures, extensive growth, and potential for substantial disfigurement and speech dysfunction. Complete surgical resection is the current standard of care; however, the procedures are often technically challenging and are followed by high recurrence ...

Abstract Number: LB-1
Presentation Title: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients
Presentation Time: Sunday, Apr 03, 2011, 10:30 AM -10:50 AM
Location: West Hall D, Orange County Convention Center
Author Block: Jean Y. Tang, Julian M. Mackay-Wiggan, Michelle Aszterbaum, Joselyn Lindgren, Kris Chang, Carol Coppola, Angela Campbell, Anita Chanana, Jackleen Marji, Chris Callahan, Robert Yauch, David R. Bickers, Ervin H. ...

Itraconazole, is an already approved drug as an oral antifungal but it has been show by a research team to also inhibit the Hh pathway. It was also shown to inhibit the pathway differently than the current SMO inhibitors in the clinic.

http://clinicaltrials.gov/ct2/show/NCT01108094

BCCs are the most common human cancer in the US and affect over 1 million people. There is no effective drug to prevent basal cell carcinomas ...

NEW ORLEANS - An oral inhibitor of the hedgehog pathway proved dramatically effective for the treatment and prevention of basal cell carcinomas in patients with basal cell nevus syndrome in a phase II study.

Indeed, the randomized double-blind trial was halted early for ethical reasons because patients assigned to vismodegib, formerly known as GDC-0449, demonstrated a 25-fold reduction in the rate of new basal cell carcinomas (BCCs), compared with placebo-treated controls, Dr. Jean Y. Tang ...

CUDC-907 is an orally bioavailable, multi-targeted small molecule that is designed to inhibit HDAC and PI3K, the combination of which Curis scientists believe have synergistic interaction against cancer cells. In vitro mechanism of action studies demonstrate that CUDC-907 is able to inhibit Class I PI3K and upregulate molecules involved in cancer cell death. CUDC-907 has also demonstrated the ability to suppress multiple nodes of other survival pathways as a result of the epigenetic modification resulting ...

A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies P1
http://clinicaltrials.gov/ct2/show/NCT01204073
This is the first study in which TAK-441 is administered to humans. The patient population will consist of adults aged 18 or older who have advanced nonhematologic malignancies and for whom standard treatment is no longer effective or does not offer curative or life-prolonging potential. Following completion of the dose escalation study, patients will be enrolled as part of 2 expansion cohorts. ...

Activation of the PI3K-AKT-mTOR signaling pathway plays a crucial role in cancer
development and progression. Recently, the inhibition of this pathway has been
extensively investigated as a potential cancer therapy. However, primary or
acquired resistance may present a major challenge to the success of inhibitors
targeting this pathway due to the existence of redundant and compensatory
pathways in cancer cells. In an effort to enhance anti-tumor activity and overcome
these limitations, we have therefore designed ...

"Recent Evidence has established Src Family Kindases as a critical component of multipule signaling pathways that regulate proliferation survival, angiogenesis and metastasis..... Synergy between HDAC and Src inhibition has been demonstrated in cancer cell lines. CU-201 is a single small molecule to inhibit HDAC, Src, and BCR-Abl. Here we report its activity in hematologic and solid tumor cell lines and in vivo"

Conclusions:

• CU-201 is a potent inhibitor of HDAC, Src and Bcr-Abl
• It exhibits ...