A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation.

RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.

Adaptive Bayesian variable clustering via structural learning of breast cancer data.

The clustering of proteins is of interest in cancer cell biology. This article proposes a hierarchical Bayesian model for protein (variable) clustering hinging on correlation structure. Starting from a multivariate normal likelihood, we enforce the clustering through prior modeling using angle-based unconstrained reparameterization of correlations and assume a truncated Poisson distribution (to penalize a large number of clusters) as prior on the number of clusters. The posterior distributions of the parameters are not in explicit form and we use a reversible jump Markov chain Monte Carlo based technique is used to simulate the parameters from the posteriors. The end products of the proposed method are estimated cluster configuration of the proteins (variables) along with the number of clusters. The Bayesian method is flexible enough to cluster the proteins as well as estimate the number of clusters. The performance of the proposed method has been substantiated with extensive simulation studies and one protein expression data with a hereditary disposition in breast cancer where the proteins are coming from different pathways.

A Dinickel Catalyzed Cyclopropanation without the Formation of a Metal Carbene Intermediate.

(NDI)Ni2 catalysts (NDI=naphthyridine-diimine) promote cyclopropanation reactions of 1,3-dienes using (Me3 Si)CHN2 . Mechanistic studies reveal that a metal carbene intermediate is not part of the catalytic cycle. The (NDI)Ni2 (CHSiMe3 ) complex was independently synthesized and found to be unreactive toward dienes. Based on DFT models, we propose an alternative mechanism that begins with a Ni2 -mediated coupling of (Me3 Si)CHN2 and the diene. N2 extrusion followed by radical C-C bond formation generates the cyclopropane product. This model reproduces the experimentally observed regioselectivity and diastereoselectivity of the reaction.

Carbene Formation and Transfer at a Dinickel Active Site.

The synthesis and reactivity of a dinickel bridging carbene is described. The previously reported [ i-PrNDI]Ni2(C6H6) complex (NDI = naphthyridine-diimine) reacts with Ph2CN2 to generate a metastable diazoalkane adduct, which eliminates N2 at 60 °C to yield a paramagnetic Ni2(µ-CPh2) complex. The Ni2(µ-CPh2) complex undergoes carbene transfer to t-BuNC via an initial isonitrile adduct, which, upon heating, releases free t-BuNCCPh2. Based on this sequence of stoichiometric reactions, a catalytic carbene transfer reaction is demonstrated.

A Terminal Iron(IV) Nitride Supported by a Super Bulky Guanidinate Ligand and Examination of Its Electronic Structure and Reactivity.

Utilizing the bulky guanidinate ligand [LAr*]- (LAr* = (Ar*N)2C(R), Ar* = 2,6-bis(diphenylmethyl)-4-tert-butylphenyl, R = NCtBu2) for kinetic stabilization, the synthesis of a rare terminal Fe(IV) nitride complex is reported. UV irradiation of a pyridine solution of the Fe(II) azide [LAr*]FeN3(py) (3-py) at 0 °C cleanly generates the Fe(IV) nitride [LAr*]FeN(py) (1). The 15N NMR spectrum of the 115N (50% Fe≡15N) isotopomer shows a resonance at 1016 ppm (vs externally referenced CH3NO2 at 380 ppm), comparable to that known for other terminal iron nitrides. Notably, the computed structure of 1 reveals an iron center with distorted tetrahedral geometry, τ4 = 0.72, featuring a short Fe≡N bond (1.52 Å). Inspection of the frontier orbital ordering of 1 shows a relatively small HOMO/LUMO gap with the LUMO comprised by Fe(dxz,yz)N(px,y) π*-orbitals, a splitting that is manifested in the electronic absorption spectrum of 1 (λ = 610 nm, ε = 1375 L·mol-1·cm-1; λ = 613 nm (calcd)). Complex 1 persists in low-temperature solutions of pyridine but becomes unstable at room temperature, gradually converting to the Fe(II) hydrazide product [κ2-(tBu2CN)C(η6-NAr*)(N-NAr*)]Fe (4) upon standing via intramolecular N-atom insertion. This reactivity of the Fe≡N moiety was assessed through molecular orbital analysis, which suggests electrophilic character at the nitride functionality. Accordingly, treatment of 1 with the nucleophiles PMe2Ph and Ar-N≡C (Ar = 2,6-dimethylphenyl) leads to partial N-atom transfer and formation of the Fe(II) addition products [LAr*]Fe(N═PMe2Ph)(py) (5) and [LAr*]Fe(N═C═NAr)(py) (6). Similarly, 1 reacts with PhSiH3 to give [LAr*]Fe[N(H)(SiH2Ph)](py) (7) which Fukui analysis shows to proceed via electrophilic insertion of the nitride into the Si-H bond.

Advances in Guanidine Ligand Design: Synthesis of a Strongly Electron-Donating, Imidazolin-2-iminato Functionalized Guanidinate and its Properties on Iron.

Imidazolin-2-imines (ImRN-), derived from N-heterocylic carbenes, have been shown to be strong electron donors when directly coordinated to metals or when used as a substituent in larger ligand frameworks. In an attempt to enhance the electron-donating properties of the popular guanidine ligand class, the effect of appending an ImRN- backbone onto a guanidinate scaffold was investigated. Addition of 1 equiv of [Li(Et2O)][Im tBuN] to the aryl carbodiimide (dippN)2C (dipp = 2,6-diisopropylphenyl) cleanly affords the lithium Im tBuN-functionalized guanidinate [Li(THF)2][(Im tBuN)C(Ndipp)2] (1). Subsequent metalation of the ligand with FeBr2 gives the yellow Fe(II) complex {[(Im tBuN)C(Ndipp)2]FeBr}2 (4) in good yield. Solid-state structural analyses of both 1 and 4 shows the Im tBuN- group acts as a non-coordinating backbone substituent. Direct structural comparison of 4 to the closely related guanidinate and ketimine-guanidinate complexes {[(X)C(Ndipp)2]FeBr}2 (X = t Bu2C=N (5); N( i Pr)2 (6)), differing only in their backbone, reveals a detectable resonance contribution of the Im tBuN- group to the guanidinate ligand electronic structure. Moreover, the Fe(II)/Fe(III) redox couple of 4 (E1/2 = -0.67 V) is cathodically shifted by greater than 200 mV from the oxidation potentials of 5 (E1/2 = -0.42 V) and 6 (E1/2 = -0.45 V), demonstrating the [(Im tBuN)C(Ndipp)2]- system to be a quantifiably superior electron donor.

Donor Properties of a New Class of Guanidinate Ligands Possessing Ketimine Backbones: A Comparative Study Using Iron.

Addition of 1 equiv of LiN═C(t)Bu2 or LiN═Ad (Ad = 2-adamantyl) to the aryl carbodiimide C(NDipp)2 (Dipp = 2,6-diisopropylphenyl) readily generates the lithium ketimine-guanidinates Li(THF)2[(X)C(NDipp)2] (X = N═C(t)Bu2 (1-(t)Bu), N═Ad (1-Ad)) in excellent yields. These new ligands can be readily metalated with iron to give the N,N'-bidentate chelates [{(X)C(NDipp)2}FeBr]2 (X = N═C(t)Bu2 (5-(t)Bu), N═Ad (5-Ad)), in which the ketimines behave as noncoordinating backbone substituents. In an effort to understand the potential electronic contributions of the ketimine group to the ligand architecture, a thorough structural and electronic study was conducted comparing the features and properties of 5-(t)Bu and 5-Ad to their guanidinate and amidinate analogues [{(X)C(NDipp)2}FeBr]2 (X = (i)Pr2N (6), (t)Bu (7)). Solid-state structural analyses indicate little electronic contribution from the N-ketimine nitrogen atom, while solution-phase electronic absorption spectra of 5-(t)Bu and 5-Ad are qualitatively similar to the amidinate complex 7. Yet, electrochemical measurements do show the donor properties of the ketimine-guanidinate in 5-(t)Bu to be intermediate between its guanidinate and amidinate counterparts in 6 and 7. Preliminary reactivity studies also show that the reduction chemistry of 5-(t)Bu diverges significantly from that of 6 and 7. Treatment of 5-(t)Bu with excess magnesium or 1 equiv of KC8 leads to the formation of the Fe(I)-Fe(I) complex [{µ-((t)Bu2C═N)C(NDipp)2}2Fe2] (11), which possesses an exceedingly short Fe═Fe bond (2.1516(5) Å), while neither 6 nor 7 forms dinuclear complexes upon reduction. This result demonstrates that ketimine-guanidinates do not simply behave as amidinate variants but can contribute to distinctive metal chemistry of their own.

Synthesis of a "super bulky" guanidinate possessing an expandable coordination pocket.

Friedel-Crafts alkylation of 4-tert-butylaniline with 2 equiv of benzhydrol affords bulky 2,6-bis(diphenylmethyl)-4-tert-butylaniline (Ar*NH2) in good yield, which can be readily synthesized on a tens of grams scale. The reaction of 6 equiv of Ar*NH2 with triphosgene generates the symmetric urea (Ar*NH)2CO, which, upon dehydration with a P2O5/Al2O3 slurry in pyridine, produces the sterically encumbered carbodiimide (Ar*N)2C as an air-stable white solid. The treatment of (Ar*N)2C with LiN═C(t)Bu2 in tetrahydrofuran cleanly gives the monomeric lithium guanidinate Li[(Ar)*ketguan], free of coordinating solvent, in 85% yield. Protonation of Li[(Ar)*ketguan] with lutidinium chloride produces the guanidine (Ar)*ketguanH (MW = 1112.60 g/mol), which is easily derivatized to give the monomeric alkali metal complexes M[(Ar)*ketguan] (M = K, Cs) in 94% and 51% yield, respectively. The solid-state molecular structures of M[(Ar)*ketguan] (M = Li, K, Cs) show formally two-coordinate alkali metal cations encapsulated within a hydrophobic coordination pocket formed by the peripheral diphenylmethyl substituents of the guanidinate. Remarkably, percent buried volume analyses (% V(Bur)) of M[(Ar)*ketguan] [M = Li (94.8% V(Bur)), K (92.1% V(Bur)), Cs (81.7% V(Bur))] reveal a coordination cavity that adjusts to individually accommodate the variously sized metal ions despite the highly encumbering nature of the ligand. This demonstrates a flexible ligand framework that is able to stabilize low-coordinate metal centers within a "super bulky" coordination environment.