Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.

Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds.

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.

Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors.

Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A-B-C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A-B-C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.

Mono(NCN-pincer palladium)-metalloporphyrin catalysts: evidence for supramolecular bimetallic catalysis.

The synthesis and catalytic properties of ditopic mono-pincer-mono-porphyrin complexes were investigated. The statistical Adler condensation reaction of 3,5-bis(methoxymethyl)-4-bromo-benzaldehyde, p-tolylaldehyde, and pyrrole, furnished an AB(3)-type tetraphenylporphyrin, containing three meso-p-tolyl groups and one meso-3,5-bis(methoxymethyl)-4-bromophenyl group. This material was converted into the ditopic ligand [2H(Br)], which comprises one porphyrin site and an NCN-pincer type ligand moiety. In order to metalate this compound in a stepwise, site-selective manner, two distinct synthetic routes were followed. Route A relies on the introduction of a metal in the porphyrin cavity followed by pincer metalation and a reversal of this order is employed for route B. For the hetero-bimetallic pincer-porphyrin target compounds, route A invariably proved to be the highest yielding alternative, giving pincer-porphyrin hybrids of general formula [M(1)(M(2)X)] (M(1) = 2H, Mg, Co, Ni, Zn; M(2) = Pd, Br; X = Cl, Br). (195)Pt NMR spectroscopy revealed that the porphyrin metal has a modest influence on the electron density on the NCN-pincer Pt site. When the analogous cationic Pd complexes were used as Lewis acid catalysts for the double Michael addition between methyl vinyl ketone and ethyl alpha-cyanoacetate, it was noted that the catalytic activity did not depend on the central metal for M(1) = 2H, Ni, and Zn. However, when Mg occupied the porphyrin cavity, the rate of the reaction increased by a factor of six. Although a rate enhancement was observed when catalysis was conducted with a mixture of the two constituents of [Mg(PdOH(2))]BF(4) (i.e. MgTTP and [PdOH(2)(NCN)]BF(4)) this could not fully account for the rate enhancement. We believe that the rationale for this behaviour is dual, consisting of "cooperative dual catalysis" and supramolecular aggregation of two or more catalyst-substrate complexes.

Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group.

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.

Synthesis of and evidence for electronic communication within heteromultimetallic tetrakis(NCN-pincer metal)-(metallo)porphyrin hybrids.

Several heteromultimetallic pincer-porphyrin hybrids have been prepared in excellent yields by stepwise metalation of a general precursor, [2H(Br(NCN))(4)], which was designed in such a way so as to guarantee selectivity for either the porphyrin or pincer sites during the metalation steps. First, a metal was introduced in the porphyrin cavity using a metal(II) salt, followed by metalation of the pincer units through oxidative addition to an appropriate metal(0) complex. The resulting multimetallic complexes show an appreciable amount of intramolecular communication between the meso-pincer metal groups and the central metalloporphyrin component. This was manifested in changes of the optical and ligand-binding properties of the metalloporphyrin part upon reactions at the peripheral pincer sites.

BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring.

We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring.

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

Merging porphyrins with organometallics: synthesis and applications.

The coordination chemistry of porphyrins has traditionally involved the ability of the porphyrin's tetrapyrrolic core to accommodate metal ions of varying charges and sizes, and on the organometallic chemistry of the resulting metalloporphyrins. However, the organometallic chemistry of porphyrins is not necessarily restricted to the metal bound in the porphyrin core, but can also be extended to the porphyrin periphery, be it through direct metalation of the porphyrin macrocycle at the meso or beta position, or by attachment to or merger of the porphyrin skeleton with ligands, followed by metalation. This Review focuses on the synthetic strategies used for porphyrins with peripheral metal-carbon bonds. The exciting results that have been produced underscore the importance and future potential of this field.

Efficient exciton transport in layers of self-assembled porphyrin derivatives.

The photosynthetic apparatus of green sulfur bacteria, the chlorosome, is generally considered as a highly efficient natural light-harvesting system. The efficient exciton transport through chlorosomes toward the reaction centers originates from self-assembly of the bacteriochlorophyll molecules. The aim of the present work is to realize a long exciton diffusion length in an artificial light-harvesting system using the concept of self-assembled natural chlorosomal chromophores. The ability to transport excitons is studied for porphyrin derivatives with different tendencies to form molecular stacks by self-assembly. A porphyrin derivative denoted as ZnOP, containing methoxymethyl substituents ({meso-tetrakis[3,5-bis(methoxymethyl)phenyl]porphyrinato}zinc(II)) is found to form self-assembled stacks, in contrast to a derivative with tert-butyl substituents, ZnBuP ({meso-tetrakis[3,5-bis(tert-butyl)phenyl]porphyrinato}zinc(II)). Exciton transport and dissociation in a bilayer of these porphyrin derivatives and TiO2 are studied using the time-resolved microwave conductivity (TRMC) method. For ZnOP layers it is found that excitons undergo diffusive motion between the self-assembled stacks, with the exciton diffusion length being as long as 15 +/- 1 nm, which is comparable to that in natural chlorosomes. For ZnBuP a considerably shorter exciton diffusion length of 3 +/- 1 nm is found. Combining these exciton diffusion lengths with exciton lifetimes of 160 ps for ZnOP and 74 ps for ZnBuP yields exciton diffusion coefficients equal to 1.4 x 10(-6) m2/s and 1 x 10(-7) m2/s, respectively. The larger exciton diffusion coefficient for ZnOP originates from a strong excitonic coupling for interstack energy transfer. The findings show that energy transfer is strongly affected by the molecular organization. The efficient interstack energy transfer shows promising prospects for application of such self-assembled porphyrins in optoelectronics.

One-dimensional, cofacial porphyrin polymers formed by self-assembly of meso-tetrakis(ERE donor) zinc(II) porphyrins.

A series of meso-tetrakis-(ERE donor) zinc(II) porphyrins nZn (ERE donor = 4-R-3,5-bis[(E)-methyl]phenyl; 1Zn: E = NMe2, R = Br; 2Zn: E = NMe2, R = H; 3Zn: E = OMe, R = Br; 4Zn: E = OMe, R = H) have been synthesized in excellent yields. As a result of the combination of a Lewis acidic site and eight Lewis basic sites within one molecule, monomeric molecules of nZn self-assemble to form one-dimensional porphyrin polymers [nZn](infinity) in the solid state, as confirmed for 1Zn and 3Zn by X-ray crystallography. The coordination environment around the zinc(II) ions in these polymers is octahedral. They are ligated by four equatorial nitrogen atoms of the porphyrin and two apical E atoms (E = N, O) provided by the EBrE donor groups of adjacent nZn molecules. Complexes 2Zn and 4Zn did not form single crystals, but solid-state UV/Vis analysis points to the formation of similar structures. Solution UV/Vis and 1H NMR spectroscopy indicated that interactions between 1Zn and 2Zn monomers in the polymers are stronger than between 3Zn and 4Zn monomers. Interestingly, they also revealed that the presence of a neighboring bromine atom in the EBrE donor groups has a considerable influence on the coordination properties of the benzylic N or O atoms. The zinc(II) ions of the porphyrins most likely adopt only hexacoordination in the solid state, owing to the unique predisposition of Lewis acidic and basic sites in the nZn molecules. Several parameters of the aggregates, for example, the interplanar separation between porphyrins and the zinc-zinc distances, change as a function of the coordinating E groups. The high degree of modularity in their synthesis makes these zinc(II) porphyrins an interesting new entry in noncovalent multiporphyrin assemblies.

"Click" 1,2,3-triazoles as tunable ligands for late transition metal complexes.

The potential of "click" 1,2,3-triazoles to act as mono-dentate ligands in late transition metal complexes is explored relative to other commonly-used Lewis bases and it is shown that their coordination strength, determined by their 1- and 4-substituents, is easily tunable.

Pincer-porphyrin hybrids.

[reaction: see text] Starting from tetrakis(3,5-bis(bromomethyl)phenyl)porphyrin, pincer-porphyrin hybrid molecules (tetrakis(ECE-pincer)porphyrin; E = N, P, S) based on a tetraphenylporphyrin skeleton have been prepared in high yields. These multi-ligand site compounds could be selectively metalated at their peripheries, which was shown by X-ray crystallography.