Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

Yan, Wei; Lakkaniga, Naga Rajiv; Carlomagno, Francesca; Santoro, Massimo; McDonald, Neil Q.; Lv, Fengping; Gutta, Naresh; Frett, Brendan; Li, Hong Yu

doi:10.1021/acs.jmedchem.8b01092

Cited by 65 publications

(41 citation statements)

References 214 publications

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“…When the kinase is in its inactive conformation, however, an “allosteric” pocket opens up behind the DFG motif, also referred as the “back pocket” [26]. Allosteric‐site inhibitors targeting this pocket were previously discovered for several kinases including Akt [27], TrkA [28], and Abl [29]. Since most kinases share structural similarity at the active site, compounds targeting any active site may result in adverse off‐target effects, whereas allosteric inhibitors are expected to be relatively specific to individual kinases.…”

Section: Discussionmentioning

confidence: 99%

FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

Balasubramaniam

Lakkaniga

Dera

et al. 2020

Biotech and App Biochem

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Akt, a serine‐threonine protein kinase, is regulated by class‐I PI3K signaling. Akt regulates a wide variety of cell processes including cell proliferation, survival, and angiogenesis through serine/threonine phosphorylation of downstream targets including mTOR and glycogen‐synthase‐kinase‐3‐beta (GSK3β). Targeting cancer‐specific overexpression of Akt protein could be an efficient way to control cancer‐cell proliferation. However, the ATP‐competitive inhibitors are challenged by the highly conserved ATP binding site, and by competition with high cellular concentrations of ATP. We previously developed an allosteric inhibitor, 2‐arylidene‐4, 7‐dimethyl indan‐1‐one (FXY‐1) that showed promising activity against several lung cancer models. In this work, we designed a congeneric series of molecules based on FXY‐1 and optimized lead based on computational, in vitro assays. Computational screening followed by enzyme‐inhibition and cell‐proliferation assays identified a derivative (FCX‐146) as a new lead molecule with threefold greater potency than the parent compound. FCX‐146 increased apoptosis in HL‐60 cells, mediated in part through decreased expression of antiapoptotic Bcl‐2 protein and increased levels of Bax‐2 and Caspase‐3. Molecular‐dynamic simulations showed stable binding of FCX‐146 to an allosteric (i.e., noncatalytic) pocket in Akt. Together, we propose FCX‐146 as a potent second‐generation arylidene indanone compound that binds to the allosteric pocket of Akt and potently inhibits its activation.

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Section: Discussionmentioning

confidence: 99%

FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

Balasubramaniam

Lakkaniga

Dera

et al. 2020

Biotech and App Biochem

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“…Encouraged by preclinical studies, different pharmaceuti cal companies have invested considerable resources in im proving kinases inhibitors, some of which are currently under clinical trials or investigations for a broad range of diseases, including oncological disorders and pain (for review [184,[193][194][195][196]). Although most of them exhibit high potency in vitro, yet the development of a TrkB inhibitor as a mar keted product has not been successful at present.…”

Section: Iii-interfering With the Itracellular Kinase Domainmentioning

confidence: 99%

Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

Ferrini

Salio

Boggio

et al. 2021

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: The growth factors BDNF and GDNF are gaining more and more attention as modulators of synaptic transmission in the mature central nervous system (CNS). The two molecules undergo a regulated secretion in neurons and may be anterogradely transported to terminals where they can positively or negatively modulate fast synaptic transmission. There is today wide consensus on the role of BDNF as a pro-nociceptive modulator, as the neurotrophin has an important part in the initiation and maintenance of inflammatory, chronic, and/or neuropathic pain at peripheral and central level. At spinal level, BDNF intervenes in the regulation of chloride equilibrium potential, decreases the excitatory synaptic drive to inhibitory neurons, with complex changes in GABAergic/glycinergic synaptic transmission, and increases excitatory transmission in the superficial dorsal horn. Differently from BDNF, the role of GDNF still remains to be unraveled in full. This review resumes the current literature on the interplay between BDNF and GDNF in the regulation of nociceptive neurotransmission in the superficial dorsal horn of the spinal cord. We will first discuss the circuitries involved in such a regulation, as well as the reciprocal interactions between the two factors in nociceptive pathways. The development of small molecules specifically targeting BDNF, GDNF and/or downstream effectors is opening new perspectives for investigating these neurotrophic factors as modulations of nociceptive transmission and chronic pain. Therefore, we finally will consider the molecules of (potential) pharmacological relevance for tackling normal and pathological pain.

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“…In 2018, the first TRK inhibitor, larotrectinib, was approved for treatment of adult and paediatric TRK fusion-positive cancer 29 . Subsequently, two other TRK TKIs, entrectinib and selitrectinib, have been evaluated in clinical trials and entrectinib has been approved for solid tumours that display TRK rearrangements 30 – 33 . Vandetanib and cabozantinib, with inhibitory activity against RET, VEGFR2 and other targets, have been approved for their ability to improve progression-free survival of MTC patients 34 , 35 and tested in other RET-driven cancers 36 , 37 .…”

Section: Introductionmentioning

confidence: 99%

Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases

Moccia

Yang

Lakkaniga

et al. 2021

Sci Rep

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We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50 < 1 nM) TRKA/B/C inhibitor. Pz-1 potently inhibited proliferation of human cancer cells carrying either RET- or TRKA oncoproteins (IC50 ~ 1 nM), with a negligible effect against RET- and TRKA-negative cells. By testing mutations, known to mediate resistance to other compounds, RET G810R/S, but not L730I/V, E732K, V738A and Y806N, showed some degree of resistance to Pz-1. In the case of TRKA, G595R and F589L, but not G667C, showed some degree of resistance. In xenograft models, orally administered Pz-1 almost completely inhibited RET- and TRKA-mutant tumours at 1–3 mg/kg/day but showed a reduced effect on RET/TRKA-negative cancer models. The activity, albeit reduced, on RET/TRKA-negative tumours may be justified by VEGFR2 inhibition. Tumours induced by NIH3T3 cells transfected by RET G810R and TRKA G595R featured resistance to Pz-1, demonstrating that RET or TRKA inhibition is critical for its anti-tumourigenic effect. In conclusion, Pz-1 represents a new powerful kinase inhibitor with distinct activity towards cancers induced by oncogenic RET and TRKA variants, including some mutants displaying resistance to other drugs.

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Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

Cited by 65 publications

References 214 publications

FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases

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