Karen Miller-Moslin

Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof‐of‐concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1) the various types of biological assays and in vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2) Smo inhibitors reported to date, including recent clinical results where available; and 3) efforts toward the identification and characterization of inhibitors of other members of the Hh pathway.

1-Amino-4-benzylphthalazines as Orally Bioavailable Smoothened Antagonists with Antitumor Activity

Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.

Discovery of NVP-LEQ506, a Second-Generation Inhibitor of Smoothened

Inhibition of the Hedgehog (Hh) pathway targeting the Smoothened receptor has proven therapeutic benefit for the treatment of Hh-dependent cancers. Lead optimization provided a novel type of Smoothened inhibitor based on a pyridazine core resulting in the clinical compound NVP-LEQ506. This new agent combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in preclinical rodent tumor models of medulloblastoma. Activity against a Smo mutant conferring resistance observed in a clinical trial with a competitor compound suggests additional therapeutic potential.

The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Regioselectivity and Enantioselectivity in Nickel-Catalysed Reductive Coupling Reactions of Alkynes

Nickel-catalysed reductive coupling reactions of alkynes have emerged as powerful synthetic tools for the selective preparation of functionalized alkenes. One of the greatest challenges associated with these transformations is control of regioselectivity. Recent work from our laboratory has provided an improved understanding of several of the factors governing regioselectivity in these reactions, and related studies have revealed that the reaction mechanism can differ substantially depending on the ligand employed. A discussion of stereoselective transformations and novel applications of nickel catalysis in coupling reactions of alkynes is also included.

A method for estimating the risk of drug-induced phototoxicity and its application to smoothened inhibitors

The energy difference between the frontier-orbital HOMO–LUMO gaps calculated for the ground state of marketed oral drugs correlated with their observed phototoxicity. This molecular descriptor, together with their maximal molar absorptivity for UV light above 290 nm, can be used to predict phototoxicity risks. This is demonstrated for the phototoxicity mitigation of 1-piperazinyl phthalazines, a class of smoothened inhibitors.

Chapter 16 Hedgehog Signaling Pathway Inhibitors as Cancer Therapeutics

Publisher Summary This chapter describes the mechanism of action of the Hedgehog (Hh) inhibitors. The Hh pathway directs the development of multiple tissues during embryonic development and contributes to tissue homeostasis in adults. The inactivation of the pathway during embryonic development causes birth defects, whereas abnormal activation is linked to tumorigenesis in several cancers. Genetic validation of this pathway in human tumors comes from the observations that patients with a germ line mutation in Patched (Ptch1)—a component of the Hh pathway—have activated Hh signaling and develop Gorlin syndrome, also known as “nevoid basal cell carcinoma (BCC).” In addition, the aberrant activation of the Hh pathway without known mutation is implicated in a number of additional tumor types, including small cell lung cancer, gut-related tumors, and pancreatic and prostate cancer. The inhibition of the Hh pathway in either tumor cells directly or non-malignant stromal cells, which as part of the tumor microenvironment support tumor growth, has emerged as an attractive target in anticancer therapy.