Drugs in Clinical Pipeline: AZD2932

AZD2932 [2-(4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)acetamide] is a potent and mutil-targeted protein tyrosine kinase inhibitor with IC₅₀ of 8 nM, 4 nM, 7 nM, and 9 nM for VEGFR-2, PDGFR-β, Flt-3, and c-Kit, respectively [1].

AZD2932 does not inhibit the various cytochrome P450 isoforms with the worst IC₅₀ being against 2C9 (IC₅₀ = 8.0 uM). It has a good fraction unbound between 3.3% free in human and 7.0% in dog sera and has no activity against hERG (IC₅₀ = 137 uM).

AZD2932 belong to the quinazoline family of kinase inhibitors, where fine-tuning of the lipophilicity of the pyrazole series provided a balanced 1:1 ratio of activity vs both VEGFR-2 and PDGFR-β. Moreover, AZD2932 potently inhibited both PDGFR-α (IC₅₀ = 2 nM) and PDGFR-β (IC₅₀ = 4 nM) phosphorylation with a correlation close to 1:1.

Common Name: AZD2932

Synonyms: AZD2932; AZD 2932; AZD-2932

IUPAC Name: 2-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)acetamide

CAS Number: 883986-34-3

SMILES:COC1=CC2=C(C(OC3=CC=C(CC(NC4=CN(C(C)C)N=C4)=O)C=C3)=NC=N2)C=C1OC

Mechanism of Action: Kinase Inhibitor; Multi-Kinase Inhibitor; KDR Inhibitor;  PDGFR Inhibitor; Angiogenesis Inhibitor

Indication: Various Cancers; Anti-tumor Therapy

Development Stage: Pre-Clinical

Company: AstraZeneca

References:
1. Ple, P. A.; et. al. Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases. Bioorg Med Chem Lett 2012, 22(1), 262-266.

Drugs in Clinical Pipeline: AC710

AC710 [N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-5-((1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy)picolinamide] is a potent, selective PDGFR-family kinases inhibitor with IC₅₀ of 7.7 nM against PDGFRβ. AC710 has the K_d values of 0.6 nM/1.0 nM/1.3 nM/1.0 nM for FLT3/KIT/PDGFRα/PDGFRβ respectively.

AC710 was very selective across the entire panel of 386 unique kinases as demonstrated by the very low S(10) scores and more than 30-fold selectivity over any other non-PDGFR kinases. Secondly, AC710 has very similar binding affinities for the PDGFR-family kinases. FLT3 appeared to be the target that was more potently inhibited by AC710. Moreover, KIT, PDGFR, and CSF1R were equally inhibited by AC710, with slightly more potency in inhibiting KIT phosphorylation. AC710 also showed clean cytochrome P450 inhibition profiles (IC50 values > 40 µM) against a panel of five isoforms (1A2, 2C9, 2C19, 2D6, and 3A4). No Cyp induction was observed for AC710 when tested at 3 and 30 µM concentrations against three isoforms (1A2, 2D6, and 3A4) [1].

The activity of AC710 is as follows:

IC₅₀ (CSF1R enzyme assay) = 10.5 nM

IC₅₀ (FLT3 in MV4-11 cells) = 2 nM; K_d = 0.6 nM

IC₅₀ (KIT in H526 cells) = 1.2 nM; K_d = 1.0 nM

IC₅₀ (PDGFRβ enzyme assay) = 7.7 nM

Common Name: AC710

Synonyms:  AC710; AC 710; AC-710

IUPAC Name: N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-5-((1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy)picolinamide

CAS Number: 1351522-04-7; 1351522-05-8 (mesylate)

SMILES:CCN1C(CC(CC1(C)C)OC2=CN=C(C=C2)C(=O)NC3=CC=C(C=C3)NC(=O)NC4=NOC(=C4)C(C)(C)C)(C)C

Mechanism of Action: Kinase Inhibitor; PFKFB3 Inhibitor

Indication: Various Cancers; Inflammatory Arthritis

Development Stage: Investigational

Company: Ambit Biosciences

Novel small molecule inhibitors targeting both FLT3 and CSF1R can be developed for either FLT3-ITD+ AML or cancer bone metastasis and rheumatoid arthritis. Synergy can also potentially be realized for autoimmune diseases by inhibiting both FLT3 and CSF1R simultaneously. A number of dual FLT3 and CSF1R inhibitors are being studied in clinical settings.

The antitumor efficacy of AC710 was assessed in a subcutaneous flank-tumor xenograft model in athymic nude mice using the MV4-11cell line, a human leukemia cell line that is FLT3-dependent and harbors a homozygous FLT3-ITD mutation. AC710 was dosed at 0.3, 3, and 30 mg/kg for 2 weeks. At 0.3 mg/kg of AC710, tumor growth was temporally inhibited, and growth resumed quickly thereafter. At 3 and 30 mg/kg of AC710, tumors regressed completely, and the tumor volume stayed suppressed for an extended period after dosing was halted. No body weight loss was observed in animals treated with AC710 at all doses, indicating that it is well tolerated in mice at efficacious doses [1].

AC710 was further evaluated prophylactically in a mouse collagen-induced arthritis (CIA) model. AC710 exhibited a significant impact on disease in a dose-dependent fashion, at a dose as low as 3 mg/kg for 15 days (day 0-14) as measured by paw clinical scores. At 10 and 30 mg/kg, AC710 demonstrated equivalent or slightly better efficacy in reducing the joint swelling and inflammation than dexomethasone administered at a safe dose [1].

References:

1. Liu, G.; et. al. Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases. ACS Med Chem Lett 2012, 3(12), 997-1002.

Drugs in Clinical Pipeline: Lucitanib

Lucitanib [6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide] is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR-1,2,3), vascular endothelial growth factor receptors 1 through 3 (VEGFR-1,2,3) and platelet-derived growth factor receptors alpha and beta (PDGFR- a,ß). As an inhibitor of FGFR-1,2,3, VEGFR-1,2,3 and PDGFR a/ß, and the role that each of these receptor kinases plays in tumor progression and metastasis formation, Lucitanib has the potential benefit of targeting three relevant pro-angiogenic growth factors in targeted patient populations identified by molecular markers.

Clovis Oncology holds exclusive development and commercial rights to lucitanib on a global basis, excluding China. Lucitanib rights to markets outside of the U.S. and Japan have been sublicensed to Les Laboratoires Servier (Servier).

Common Name: Lucitanib
Synonyms: CO-3810; S 80881; E-3810

IUPAC Name: 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-N- methylnaphthalene-1-carboxamide

CAS Number: 1058137-23-7
Mechanism of Action: Kinase Inhibitor; FGFR Inhibitor; VEGFR Inhibitor; PDGFR Inhibitor
Indication: Various cancers, tumors
Development Stage: Phase I/II

Company: Clovis Oncology

A Phase I/IIa clinical trial of Lucitanib was initiated in 2010 and has demonstrated multiple objective responses in FGFR1 gene-amplified breast cancer patients, and objective responses were also observed in patients with tumors often sensitive to VEGFR inhibitors, such as renal cell and thyroid cancer. FGFR amplification is common in a number of tumor types, including breast cancer and lung cancer, and it is intended to study Lucitanib in these cancers as well as other solid tumors exhibiting FGFR pathway activation. A broad Phase II development program has been initiated by Clovis and Servier in multiple indications, including advanced breast and lung cancers.