Design of Hedgehog pathway inhibitors for cancer treatment

Abstract

Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…[209] Hedgehog (Hh) signaling is responsible for pancreatic tumor initiation and progression as well as desmoplasia, which promotes both tumor growth and metastasis and hinders the delivery of chemotherapeutics. [210] Moreover, while upregulation of Hh in pancreatic cancer cells, the level of miR-let7b is downregulated. Kumar et al used mPEG-b-PCC-g-DC-g-TEPA lipopolymer to co-deliver miR-let7b and GDC-0449 which is a widely used Hh inhibitor and showed synergistic effect in pancreatic cancer cells (Capan-1, HPAF-II, T3M4, and MIA PaCa-2) and demonstrated that intratumoral administration of combination formulation into athymic nude mice bearing MIA PaCa-2 cells derived ectopic tumor significantly inhibited tumor growth.…”

“…Hedgehog (Hh) signaling is responsible for pancreatic tumor initiation and progression as well as desmoplasia, which promotes both tumor growth and metastasis and hinders the delivery of chemotherapeutics . Moreover, while upregulation of Hh in pancreatic cancer cells, the level of miR‐let7b is downregulated.…”

Synthesis and Evaluation of Aminothiazole Derivatives as Hedgehog Pathway Inhibitors

“…The Hedgehog (Hh) signaling pathway regulates cell growth and migration in developing embryo, and it is typically silent in adult tissues . Activation of Hh signaling pathway is initiated by Hh ligands bound to its receptor Patched (Ptch), which abrogates its repression of Smoothened (Smo) receptor . Smo then translocates to the primary cilia (PC) and initiates downstream Hh signaling, and the activated Gli proteins transfer into the nucleus to induce the expression of Hh target genes .…”

Características da toxicidade promovida por oxisteróis em células-tronco mesenquimais derivadas da medula óssea de pacientes com leucemia mieloide aguda

“…A LMA acomete indivíduos de todas as idades, mas a prevalência ocorre em indivíduos acima dos 60 anos de idade. O diagnóstico da LMA é realizado pela identificação de mieloblastos presentes no sangue periférico e medula óssea (Kumar et al, 2018;Löwenberg et al, 1999).…”

“…Quando ocorre a desregulação da via, há uma proliferação celular descontrolada, resultando na tumorigênese, metastase celular e contribuindo ao fenótipo de resistência de múltiplas drogas (MDR) (Bariwal et al, 2018). Determinados oxisteróis poderiam exercer um papel importante como agente e/ou adjuvante antitumoral (Aupeix et al, 1995;Olkkonen et al, 2012).…”