PF-3758309, A New Potent "PAK1/PAK4-6" Inhibitor

A group led by Brion Murray at Pfizer Oncology in San Diego recently developed
a new potent synthetic anti-cancer drug called "PF-3758309" （in short we call
「ＵＮーＰＡＫ３０９」) which inactivates selectively a few members of PAK
family kinases, namely PAK1 as well as group B PAKs (PAK 4-6). It suppresses
the growth of human cancer cells with the IC50 around 5 nM. In vivo (xenografts
in mice), it strongly suppresses the growth of several human cancers at
doses (10-20 mg/kg, twice a day, oral administration). Among the most sensitive
cancers to this drugs are colon, breast, and lung cancers as well as melanoma.
Since brain tumors such as glioma, NF (neurofibromatosis, in particular
NF2) and TSC (tuberous sclerosis) tumors require at least the oncogenic kinase
PAK1 for their growth, in principle, this drug could suppress their growth,
if it is able to pass the BBB (blood brain barrier), as does Bio 30, a CAPE
(caffeic acid phenethyl ester) -rich NZ propolis extract (25 mg/kg, oral,
daily) which selectively blocks the oncogenic PAK1 signaling. According to
Brion, an enzymologist and kinase expert, at least an analogue of this
compound passes the BBB. That is very encouraging!


新規なＰＡＫ遮断剤"PF-3758309"

今月初めに、米国カルフォルニア州サンディゴにある世界最大の製薬会社
「ファイザー」の制癌剤開発部が、新規なＰＡＫ遮断剤を開発した。化学名は
「ＰＦー３７５８３０９」(略称「ＵＮーＰＡＫ３０９」）、人工的に合成された化学薬品
で、ＰＡＫファミリーに属するキナーゼの内、主に（発癌性の強い）ＰＡＫ１と
ＰＡＫ４ー６を選択的に阻害する薬剤である。細胞培養系で、癌細胞の増殖を
極めて低濃度（ＩＣ５０＝５ ｎＭ）で阻害する。ヒト由来の癌を移植したヌード
マウスを、この薬剤で処理（経口投与、日に２回、１０ー２０mg/kg）すると、
（大腸癌、乳癌、肺癌、メラノーマなど）数種の癌が５０％以上の増殖阻害を示す。
脳腫瘍（グリオーマ、ＮＦ腫瘍、ＴＳＣ腫瘍など）の増殖は、ＰＡＫ１依存性なので、
もし、この薬剤がＢＢＢ (血液脳関門)を通過しうるならば、これらの脳腫瘍の
治療にも、将来（恐らく、臨床テストが全部完了するだろう２０２０年頃には、
世界的に市販され始め）、役立つかもしれない。。。


The Key to Survive Cancers: Un-PAK-Ing for the Longevity

Hiroshi Maruta,

NF CURE Japan, Melbourne, Australia


PREFACE:

PAK is a family of Ser/Thr kinases, present in all eukaryotes from yeast to human, that are activated by GTPases RAC and CDC42. PAK family kinases, in particular PAK1, are required for the growth of more than 70% of all human cancers, in particular solid tumors such as breast, prostate, pancreatic, colon, gastric, lung, cervical, ovarian, and thyroid cancers as well as glioma, melanoma, hepatoma, MM (multiple myeloma), NF (neurofibromatosis) and TSC (tuberous sclerosis). PAK1 is essential not only for the malignant (anchorage-independent) growth of cancer cells, but also for their metastasis and angiogenesis. Furthermore, it is not essential for the normal cell growth. Thus, synthetic chemicals or natural products, that un-PAK (block the oncogenic PAK1 signaling), would be useful for the therapy of these PAK1-dependent tumors, without any adverse effect on normal tissues. Although only a few un-PAKing (anti-PAK) chemicals such as DPM (dipyridamole), Metformin, and SAHA, are currently available on the market, a variety of natural anti-PAK products are available on the market, and the latter are very inexpensive and far safer. These include a bee product called propolis, curcumin in Indian curry, berberine, resveratrol in red grapes, capsaicin/capsiate in Chili pepper or its non-pungent variant, (Chinese or Okinawa) bitter melons, Sichuan pepper and an old antibiotic called Ivermectin.

More interestingly, these natural anti-PAK products activate another kinase called LKB1, a tumor suppressor that activates another kinase called AMPK (AMP-activated kinase), and inactivates PAK1 simultaneously. Eventually the tumor suppressive LKB1-AMPK signaling cascade activates not only GLUT-4, a glucose transporter essential for uptake of blood glucose into cells, but also the tumor suppressive transcription factor called "FOXO" which is essential for the longevity. Also AMPK activators are known to stimulate lipid metabolism (consumption). Thus, the anti-PAK products would be useful for the therapy of both type 2 (insulin-resistant) diabetes and obesity, and eventually serve as elixirs that promote the longevity in good health.

It should also be worth noting that there are several non-cancerous diseases which require the kinase PAK1: AIDS (HIV-infection), inflammatory diseases such as asthma and arthritis, neuronal degenerating diseases such as Alzheimer's (AD) and Huntington's (HD), and an autism called Fragile X-syndrome. These PAK1-dependent diseases could also be treated by these anti-PAK products. Thus, the potential market value of these anti-PAK products, either synthetic chemicals or natural products, would be huge in the future. Here an inexpensive and quick in vivo system using a tiny glowing "GFP-HSP16" nematode (CL2070) is introduced, that would facilitate the screening for anti-PAK products, and eventually could be revolutionized by the automation on 96-well micro-titer plates with a fluorescence reader.

In the end, I shall introduce two potent anti-PAK drugs, FK228 and UN-PAK309, which are in clinical trials for cancers. FK228 is the most potent HDAC (histone deacetylase) inhibitor which eventually blocks PAK1 with the IC50 far below 1 nM in cells. UN-PAK309 is the direct PAK1 inhibitor with the IC50 around 5 nM in cells. Although FK228 fails to pass the BBB (blood brain barrier), it is likely that UN-PAK309 passes the BBB, suggesting that the latter could be useful for the therapy of brain tumors such as glioma, NF and TSC tumors in the future.