Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity

McCoull, William; Hennessy, Edward J.; Blades, Kevin; Box, Matthew; Chuaqui, Claudio; Dowling, James E.; Davies, Celia; Ferguson, Andrew D.; Goldberg, Frederick W.; Howe, Nicholas J.; Kemmitt, Paul D.; Lamont, Gillian M.; Madden, Katrina S.; McWhirter, Claire; Varnes, Jeffrey; Ward, Richard A.; Williams, Jason D.; Yang, Bin

doi:10.1039/c4md00280f

Cited by 16 publications

(24 citation statements)

References 20 publications

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“…Throughout the optimization process, cellular pPAK1 inhibition was measured in an MCF10A cell line. 10 This cell potency was found to correlate well with the PAK1 enzyme activity, with a shift as expected based on different ATP concentrations in the two assays (see Supporting Information). A cross check with a similar assay measuring pPAK1 inhibition in the PAK1 amplified cell line OVCAR3 for 11 showed AZ13705339 (18) had 59 nM cellular pPAK1 potency, high selectivity against PAK4, KDR, and FGFR1, and even 14-fold selectivity against Src so was considered to be an excellent in vitro probe compound.…”

Section: Acs Medicinal Chemistry Letterssupporting

confidence: 58%

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Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

McCoull

Hennessy

Blades

et al. 2016

ACS Med. Chem. Lett.

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Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structurebased drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology. KEYWORDS: PAK, LLE, kinase selectivity, probe, bis-anilino pyrimidine T he p21-activated kinases (PAKs) are a family of six serine/ threonine-specific intracellular protein kinases that are positioned at the intersection of multiple signaling pathways of importance in cancer progression. 1,2 The PAK family comprises two subgroups based on sequence homology: group I (PAKs 1−3) and group II (PAKs 4−6). Group I PAKs have high sequence identity in the kinase domain and possess an autoinhibitory domain, which is relieved by binding of the GTP-binding proteins Rac or Cdc42, while group II PAKs have lower kinase domain homology and are not activated by Rho GTPases. 3 Group I PAKs are overexpressed in a wide variety of cancers, and PAK1 is commonly overexpressed in breast tumors with poor prognosis. 4 In ovarian cancer cells characterized by PAK1 amplification, treatment with a PAK1 inhibitor decreased proliferation and migration. 5 In tumors characterized by neurofibromatosis type 2 (NF2) inactivation, group I PAKs have been shown to be hyperactivated. 6 Consequently, there is increasing interest in identifying potent and selective small molecule inhibitors of PAK1 for therapeutic use in tumors characterized by PAK activation. 7 There are relatively few chemotypes described in the literature for PAK1 inhibitors 8 and only pan-PAK inhibitor PF-3578309 9 progressed into clinical trials but is now stopped. Ourselves 10 and others 11,12 have recently disclosed PAK1 inhibitors but achieving high kinase selectivity with a chemotype amenable to achieving oral exposure has been challenging. Without high kinase selectivity it is difficult to discern whether PAK1 is driving efficacy; thus, new alternative chemotypes for selective PAK1 inhibition are required.Following a kinase-focused subset screen (120k compounds) of the AstraZeneca compound collection, bis-anilino pyrimidine 1 (Figure 1) was identified as a modestly potent PAK1 inhibitor (IC 50 = 100 nM) with 11-fold selectivity over PAK4 (Table 1).While selectivity within the group I PAKs was not expected, PAK4 was utilized to monitor selectivity against group II PAKs. Selectivity against some key kinase antitargets, KDR and FGFR1, 13 was modest. Since 1 originated from an EphB4 kinase project, 14 a member of the Src kinase family, high activity for Src kinase was expected. Src family kinase activity was of less concern to us but was monitored as a measure of overall kinase selectivity. A crystal structure of 1 bound...

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Section: Acs Medicinal Chemistry Letterssupporting

confidence: 58%

“…A crystal structure of 1 bound to PAK1 was obtained and compared with a crystal structure of a 7-azaindole PAK1 inhibitor 2 (PAK1 IC 50 = 260 nM) previously reported by us (Figure 2). 10 Overlay of these different chemotypes allowed us to visualize four areas of structure 1 to be explored to optimize PAK1 binding.…”

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confidence: 99%

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

McCoull

Hennessy

Blades

et al. 2016

ACS Med. Chem. Lett.

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“…With a PAK1 K i of 1.6 nM and pMEK IC 50 of 43 nM, this, to the best of our knowledge, represents the most ligand-efficient 76 PAK1 inhibitor published to date (LE = 0.42). While no further details regarding kinase selectivity, ADME properties, or efficacy of this series have been reported to date, one can postulate that their pendent, generally bicyclic aromatic substituent from the 2-position of the pyrimidine ring may be 86,57 oriented toward the sugar pocket, perhaps in a similar manner to the 3-azabicyclo[3.1.0]hexan-6-amine group used in the compounds described earlier (albeit for PAK4). In a subsequent filing, Genentech reported on related compounds, this time with aza-bicyclic heterocycles at the pyrimidine 2-position.…”

Section: ■ Atp Competitive Pak Inhibitorsmentioning

confidence: 92%

“…AstraZeneca recently reported the identification of the 7-azaindole PAK1 inhibitor 28 ( Figure 17). 86 Following a screen of a kinase-focused subset of the AZ compound collection (∼120 000 compounds), biaryl ketone azaindoles were found to be potent against PAK1 and exhibit high PAK1 vs PAK4 selectivity. 2-Cl ketone 27 86 This compound binds as expected, with the donor−acceptor pair of the azaindole forming hydrogen bonds with the hinge of the kinase, while the 2-Cl-phenyl moiety resides in a selectivity pocket adjacent to the methionine gatekeeper residue, as seen with the deep-pocket binding compounds from Afraxis ( Figure 18A).…”

Section: Pyrido[23-d]pyrimidine-7-one Series (Group I Pak Inhibitorsmentioning

confidence: 99%

“…86 Following a screen of a kinase-focused subset of the AZ compound collection (∼120 000 compounds), biaryl ketone azaindoles were found to be potent against PAK1 and exhibit high PAK1 vs PAK4 selectivity. 2-Cl ketone 27 86 This compound binds as expected, with the donor−acceptor pair of the azaindole forming hydrogen bonds with the hinge of the kinase, while the 2-Cl-phenyl moiety resides in a selectivity pocket adjacent to the methionine gatekeeper residue, as seen with the deep-pocket binding compounds from Afraxis ( Figure 18A). In fact, superimposition of the PAK1 cocrystal structures of azaindole 8 and the pyrido[2,3-d]pyrimidine-7-one 7 reveals a similar positioning of the chlorophenyl moiety pointing toward the deep pocket ( Figure 18B).…”

Section: Pyrido[23-d]pyrimidine-7-one Series (Group I Pak Inhibitorsmentioning

confidence: 99%

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Inhibitors of p21-Activated Kinases (PAKs)

Rudolph¹,

Crawford²,

et al. 2014

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The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated.

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Palladium‐Catalyzed Barluenga‐Valdes Type Cross‐Coupling Reaction: Alkenylation of 7‐Azaindoles

et al. 2020

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An efficient coupling method between sulfonylhydrazones and 7-azaindoles using Pd(OAc) 2 as catalyst and dppf as ligand providing flexible and convergent access to different vinyl 7-azaindoles is achieved. A wide variety of olefins were obtained up to 86% yields via the coupling of numerous electronically distinct hydrazones with different 7-azaindoles under the present catalytic conditions. The protocol was further extended to other heteroarenes such as indoles, quinolines, isoquinolines, and pyridine. The imperative feature of these protocols is its ease at the gram scale and their potential to get transformed into different valuable constructs.

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Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity

Cited by 16 publications

References 20 publications

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

Inhibitors of p21-Activated Kinases (PAKs)

Palladium‐Catalyzed Barluenga‐Valdes Type Cross‐Coupling Reaction: Alkenylation of 7‐Azaindoles

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