Timothy B. Lowinger

Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) — from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 — was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.

Design and Discovery of Small Molecules Targeting Raf-1 Kinase

Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.

Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1

IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).

A selective novel low‐molecular‐weight inhibitor of IκB kinase‐β (IKK‐β) prevents pulmonary inflammation and shows broad anti‐inflammatory activity

1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell‐mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF‐κB). 3 NF‐κB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK‐β. 4 We identified COMPOUND A as a small‐molecule, ATP‐competitive inhibitor selectively targeting IKK‐β kinase activity with a Ki value of 2 nM. 5 COMPOUND A inhibited stress‐induced NF‐κB transactivation, chemokine‐, cytokine‐, and adhesion molecule expression, and T‐ and B‐cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS‐induced TNF‐α in rodents. 7 In mice COMPOUND A inhibited cockroach allergen‐induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed‐type hypersensitivity. 10 These data suggest that IKK‐β inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.

1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors

Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).

Discovery of a new class of p38 kinase inhibitors

The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class.

Small molecule inhibitors of IKK kinase activity

The nuclear transcription factor NF-κB plays a significant role in the pathogenesis of a variety of diseases. Because of the key role played by the inhibitor of κB kinase (IKK) complex in the activation of NF-κB, coupled with the druggability of kinases as a target class, numerous companies have been pursuing discovery programmes aimed at identifying small molecule inhibitors of these enzymes. This paper reviews the patenting activity associated with these efforts.

The total synthesis of (±)K252a

Abstract The total synthesis of (±)K252a ( 1 ) has been achieved following a convergent approach in which an acid-catalyzed bis-glycosidation reaction serves as a key step.

Antibody Drug Conjugates for Treatment of Breast Cancer: Novel Targets and Diverse Approaches in ADC Design.

Breast cancer is a heterogeneous group of malignancies with a spectrum of molecular subtypes, pathologies and outcomes that together comprise the most common non-cutaneous cancer in women. Currently, over 80% of breast cancer patients are diagnosed at relatively early stages of disease where there are encouraging data on outcomes and long term survival. However, there is currently no curative option for those patients with metastatic disease and there is a substantial medical need to identify effective and safe treatment options for these patients. One approach to improve cancer therapy is by designing therapeutics directed against targets with differential levels of expression on malignant versus normal cells with the goal of improving tumor selectivity and reducing damage to normal tissues. Antibody drug conjugates (ADCs) are a rapidly evolving therapeutic class that exploits the target-selectivity of monoclonal antibodies (MAbs) to deliver cytotoxic drugs to antigen-expressing cells (Lambert & Morris, 2017; Senter, 2009; Thomas, Teicher, & Hassan, 2016; Trail, 2013). The regulatory approval of ADCs for both hematologic malignancies (brentuximab vedotin) (Younes et al., 2010) and solid tumors (ado-trastuzumab emtansine) (Amiri-Kordestani et al., 2014; Verma et al., 2012) clearly demonstrates the clinical potential of ADCs. This review will focus on targets under consideration for breast cancer directed ADCs and on the technology modifications being considered to improve ADC efficacy and safety.

Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence.

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.