Inhibitors of p21-Activated Kinases (PAKs)

Rudolph, Joachim; Crawford, James J.; Hoeflich, Klaus P.; Wang, Weiru

doi:10.1021/jm501613q

Cited by 98 publications

(125 citation statements)

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“…The type II PAKs are also thought to have a role in invasion and metastasis (6,67,76), and PAK4 may also play a role in proliferation of BRAF-or KRAS-driven cancers (85). These discoveries have provided a framework to drive efforts to achieve ATP-competitive small molecule inhibitors of the type II PAKs (6,76,86), with PF-3758309 the most prominent example (63).…”

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

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Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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The p21-activated kinases (PAKs) are a family of six serine/ threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.The type II PAKs 2 are members of the Sterile 20 (Ste20) family of STE (homologs of yeast Sterile 7, Sterile 11, and Sterile 20) group serine/threonine kinases. They are important for signaling from small GTPases of the RHO family, particularly the CDC42 (cell division cycle 42) and to a lesser extent RAC (Rasrelated C3 botulinum toxin substrate) isoforms, to the actin cytoskeleton and to growth and survival pathways. Type II PAKs share significant sequence similarity with the well studied type I PAKs (PAK1, PAK2, and PAK3), which are extensively reviewed elsewhere (1-5), but the roles of the type I and type II PAKs in GTPase signaling pathways, and their mechanisms of regulation, differ considerably. In the sections below, we consider the function of the type II PAK serine/threonine kinases in small GTPase pathways, the structural and biochemical basis for their regulation, mechanisms of their targeting to substrates, and some of the current strategies for targeted small molecule inhibition of these enzymes. Type II PAKs in Signal TransductionThe type II PAKs are binding partners of RHO family small GTPases. Their dominant role in signal transduction is as serine/threonine kinases, where transfer of the ␥-phosphate from an ATP molecule to a substrate protein results in consequent regulation of downstream effector pathways. The activation of type II PAK kinase signaling is associated with small GTPase binding, but as discussed below, direct activation does not seem to occur upon small GTPase binding. Rather, GTPases are thought to primarily regulate type II PAKs by controlling their subcellular localization. Type II PAKs also have reported kinase-independent roles as scaffolding proteins, with functions that are still emerging.The type II PAKs are placed at critical nodal points in multiple signaling pathways that are associated with cell growth, cytoskeletal dynamics, cell polarity, survival, and development (6 -8). They are located directly downstream of RHO family GTPase activation. Numerous substrates of type II PAKs have been identified that are thought to act as downstream effectors in distinct cellular processes. For example, direct phosphorylation of LIM kinases (9, 10), p210/␤-catenin (11, 12), slingshot phosphatase (SSH) (13), 14), and PDZ-RHOGEF (15) has...

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Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

“…Structural biology is therefore aiding the progress toward PAK-specific drug discovery. The reader is also directed to further recent in-depth discussions on the roles and targeting of PAKs in disease (6,67,76,86,97).…”

Section: Alteration Of Type II Pak Signaling In Cancermentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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“…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.…”

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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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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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“…LCH-7749944 suppresses the proliferation of gastric cancer cells and mediates cell cycle arrest involving cyclin D1 repression in a human gastric cancer cell line 22. Unfortunately, a phase I study of a PAK inhibitor showed that it had low bioavailability 23. No relationship has been found between PAK4 and tyrosine kinase receptors targeted by molecular anticancer drugs such as HER2 and VEGFR2.…”

Section: Discussionmentioning

confidence: 99%