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1.
J Am Chem Soc ; 145(40): 21937-21944, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37767920

RESUMO

Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

2.
Angew Chem Int Ed Engl ; 62(18): e202302364, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-36898968

RESUMO

Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.


Assuntos
Autofagia
3.
J Org Chem ; 87(10): 6760-6768, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35486501

RESUMO

Diarylamines possess two potentially atropisomeric C-N axes; however, there are few examples of atropisomerically stable diarylamines in the literature, as the contiguous axes can allow for low energy racemization pathways via concerted bond rotations. Herein, we describe highly atropisomerically stable diarylamines that possess barriers to racemization of 30-36 kcal/mol, corresponding to half-lives to racemization on the decade to century time scale at room temperature. Investigation of the factors that led to the high stereochemical stability suggests that increased conjugation of the aniline lone pair of electrons into a more electron-deficient aryl ring, coupled with intramolecular hydrogen-bonding, locked the corresponding axis into a defined planar conformation, disfavoring the lower energy racemization pathways.


Assuntos
Elétrons , Ligação de Hidrogênio , Conformação Molecular
4.
J Am Chem Soc ; 142(5): 2198-2203, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31944689

RESUMO

Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective synthesis, as these axes typically possess lower stereochemical stabilities. Herein, we report a chiral phosphoric acid catalyzed atroposelective electrophilic halogenation of N-aryl quinoids, a class of compounds that are analogous to diarylamines. This chemistry yields a large range of stereochemically stable N-aryl quinoids in excellent yields and atroposelectivity. This work represents the first example of the atroposelective synthesis of a diarylamine-like scaffold and will serve as a gateway to fundamental and applied studies on the scarcely studied chirality of these ubiquitous chiral scaffolds.


Assuntos
Hidroquinonas/síntese química , Catálise , Hidroquinonas/química , Estereoisomerismo , Termodinâmica
5.
J Am Chem Soc ; 142(41): 17271-17276, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32981317

RESUMO

A new strategy to create highly redox-responsive H-bond dimers based on proton-coupled electron transfer is proposed that capitalizes on the importance of secondary H-bonds in determining overall binding strength in H-bond dimers. Electron transfer induced proton transfer across a H-bond can be used to significantly strengthen the overall binding by both creating strong ionic H-bonds and changing the secondary H-bonds from unfavorable to favorable. The viability and potency of this approach are demonstrated with an electroactive DAD (A = H-acceptor, D = H-donor) array, H(MQ+)H, paired with an electroinactive ADA array, O(NH)O. NMR titration of H(MQ+)H with O(NH)O in 0.1 M NBu4PF6/CD2Cl2 gives a Kassoc of 500 M-1, typical of DAD-ADA dimers. However, upon two-electron reduction in 0.1 M NBu4PF6/CH2Cl2, cyclic voltammetry studies indicate a 1.8 × 105 increase in binding strength, corresponding to a very large Kassoc of 9 × 107 M-1. The latter value is typical of DDD-AAA H-bond dimers, consistent with proton transfer across the central H-bond upon reduction.

6.
Bioorg Med Chem Lett ; 30(9): 127108, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32192797

RESUMO

Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin ß1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with the ultimate goal to pharmacologically validate this kinase as a novel target in cancer. We used a homogeneous time resolve fluorescence (HTRF) assay to screen a collection of mixture-based combinatorial chemical libraries containing over 18 million compounds. We identified several cyclic guanidine-linked sulfonamides with sub-micromolar activity and evaluated their binding mode using a 3D homology model of the LMTK3 KD.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Antineoplásicos/química , Técnicas de Química Combinatória , Descoberta de Drogas , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas
7.
ACS Med Chem Lett ; 14(3): 305-311, 2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36923918

RESUMO

Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib's predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound's selectivity toward a given target.

8.
J Med Chem ; 65(23): 15627-15641, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36416208

RESUMO

Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAKs 1-3 have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has modest potency. Here, we report the development of BJG-05-039, a PAK1-selective degrader consisting of NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon. BJG-05-039 induced selective degradation of PAK1 and displayed enhanced anti-proliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.


Assuntos
Dibenzazepinas , Pirrolidinas , Animais , Camundongos
9.
ACS Chem Biol ; 14(9): 1930-1939, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424197

RESUMO

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis; however, most small molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low-energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug-resistant epidermal growth factor receptor (EGFR) mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.


Assuntos
Receptores ErbB/antagonistas & inibidores , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Sequência de Bases , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios Enzimáticos , Receptores ErbB/genética , Humanos , Isoquinolinas/química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-ret/química , Pirimidinas/química , Pirróis/química , Estereoisomerismo
10.
Future Med Chem ; 10(4): 409-422, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29380622

RESUMO

Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. There are several examples of stable atropisomeric US FDA-approved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities. Rapidly interconverting atropisomerism is even more prevalent, and while such compounds are typically considered achiral, they bind their protein targets in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities. It has been recently demonstrated that various properties of an interconverting atropisomer can be modulated through the synthesis of atropisomer stable and pure analogs. Herein we discuss examples of atropisomerism in drug discovery as well as challenges and opportunities moving forward.


Assuntos
Química Farmacêutica , Preparações Farmacêuticas/química , Bibliotecas de Moléculas Pequenas/química , Descoberta de Drogas , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular
11.
Org Lett ; 20(7): 2037-2041, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29561161

RESUMO

The catalytic enantioselective synthesis of 3-aryl-substituted pyrrolopyrimidines (PPYs), a common motif in drug discovery, is achieved through a kinetic resolution via quaternary ammonium salt-catalyzed nucleophilic aromatic substitution (SNAr). Both enantioenriched products and starting materials can be functionalized with no observed racemization to give enantiodivergent access to diverse chiral analogues of an important class of kinase inhibitor. One of the compounds was found to be a potent and selective inhibitor of breast tumor kinase.


Assuntos
Pirimidinas/síntese química , Pirróis/síntese química , Catálise , Cátions , Estrutura Molecular , Estereoisomerismo
12.
Synlett ; 29(16): 2155-2160, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31178629

RESUMO

Herein we report studies towards a small molecule catalytic approach to access atropisomeric diaryl ethers that proceeds via a C(sp 2)-H alkylation using nitroalkanes as the alkyl source. A quaternary ammonium salt derived from quinine containing a sterically hindered urea at the C-9 position was found to effect atroposelective C(sp 2)-H alkylation with moderate to good enantioselectivities across several naphthoquinone-containing diaryl ethers. Products can then be isolated in greater than 95:5 er after one round of trituration. For several substrates that were evaluated we observed a 'nitroethylated' product in similar yields and selectivities.

13.
Chem Commun (Camb) ; 53(9): 1494-1497, 2017 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-28084476

RESUMO

Catalysts that contain a thiourea tethered to a carboxylic acid were found to affect the sulfenylation of indoles and other N-heterocycles on the hour time scale at room temperature. The mild nature of these conditions allowed for the incorporation of diverse functionalities into more complex heterocycles.

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