Qinhua Huang

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction.

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)(3) to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity

Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure.

The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).

Abstract PR10: Is CNS availability for oncology a no-brainer? Discovery of PF-06463922, a novel small molecule inhibitor of ALK/ROS1 with preclinical brain availability and broad spectrum potency against ALK-resistant mutations.

Oncogenic fusions of anaplastic lymphoma kinase (ALK) define a subset of human lung adenocarcinoma. The 1st generation ALK inhibitor crizotinib demonstrated impressive clinical benefit in ALK-fusion positive lung cancers and was approved by the FDA for the treatment of ALK-fusion positive NSCLC in 2011. However, as seen with most kinase inhibitors, patients treated with crizotinib eventually develop resistance to therapy. Acquired ALK kinase domain mutations and disease progression in the central nervous system (CNS) are reported as main contributors to patient relapse after ALK inhibitor therapy. Preclinically, crizotinib lacks significant brain penetration and does not potently inhibit activity of ALK kinase domain mutants, so a drug discovery program was initiated aimed to develop a second generation ALK inhibitor that is more potent than existing ALK inhibitors, capable of inhibiting the resistant ALK mutants and penetrating the blood-brain-barrier. These objectives present a considerable challenge in kinase inhibitor chemical space. Here we report that PF-06463922, a novel small molecule ATP-competitive inhibitor of ALK/ROS1, showed exquisite potencies against non-mutant ALK (Ki 100 fold kinase selectivity against 95% of the kinases tested in a 207 recombinant kinase panel. Specific design considerations were developed leading to novel ATP-competitive kinase inhibitors with desired low efflux in cell lines over-expressing p-glycoprotein and breast cancer resistance protein, providing excellent blood-brain-barrier and cell penetration properties. Efforts to optimize ligand efficiency and lipophilic efficiency leveraging structure based drug design techniques led to ligands with overlapping broad spectrum potency and low efflux. Single and repeat dose preclinical rat in vivo studies of PF-06463922 demonstrated excellent oral bioavailability and CNS availability with free brain exposure approximately 30% of free plasma levels. In addition, CNS-directed safety studies showed no adverse events at predicted efficacious concentrations. It is anticipated that PF-06463922 with its potent activities on non-mutant ALK, ALK kinase domain mutations and CNS metastases would provide great promise for patients with ALK and ROS1 positive cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR10. Citation Format: Ted W. Johnson, Simon Bailey, Benjamin J. Burke, Michael R. Collins, J. Jean Cui, Judy Deal, Ya-Li Deng, Martin P. Edwards, Mingying He, Jacqui Hoffman, Robert L. Hoffman, Qinhua Huang, Robert S. Kania, Phuong Le, Michele McTigue, Cynthia L. Palmer, Paul F. Richardson, Neal W. Sach, Graham L. Smith, Lars Engstrom, Wenyue Hu, Hieu Lam, Justine L. Lam, Tod Smeal, Helen Y. Zou. Is CNS availability for oncology a no-brainer? Discovery of PF-06463922, a novel small molecule inhibitor of ALK/ROS1 with preclinical brain availability and broad spectrum potency against ALK-resistant mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR10.