EXHIBIT 4.2.2 FIRST AMENDMENT TO THE AMENDED AND RESTATED INVESTOR RIGHTS AGREEMENT

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                                                                   Exhibit 4.2.2

                           SYNTA PHARMACEUTICALS CORP.

                                 FIRST AMENDMENT
                                     TO THE
                 AMENDED AND RESTATED INVESTOR RIGHTS AGREEMENT

     This First Amendment (the "AMENDMENT") to the Amended and Restated Investor
Rights Agreement, dated December 13, 2002, by and among Synta Pharmaceuticals
Corp., a Delaware corporation (the "COMPANY"), and the Investors named therein
(the "INVESTOR RIGHTS AGREEMENT"), is made as of January 11, 2005, by and among
the Company and the Investors. Capitalized terms used herein but not defined
shall have the meanings ascribed to such terms in the Investor Rights Agreement.

     WHEREAS, Section 2 of the Investor Rights Agreement sets forth certain
rights granted to the Investors with respect to the registration of the
Registrable Securities;

     WHEREAS, the Company and the Investors wish to alter the registration
rights granted to the Investors as set forth in the Investor Rights Agreement;

     WHEREAS, the Company wishes to grant these registration rights to an
additional Investor by adding an additional party to the Investor Rights
Agreement, and the Company and the Investors wish to amend the Investor Rights
Agreement to add such additional Investor;

     WHEREAS, Section 4 of the Investor Rights Agreement sets forth certain
rights granted to the Investors with respect to the right of first refusal to
purchase certain securities issued by the Company;

     WHEREAS, the Company and the Investors wish to amend the Investor Rights
Agreement to provide that the rights set forth in Section 4 terminate upon the
closing of an Initial Offering; and

     WHEREAS, in accordance with Section 5.7 of the Investor Rights Agreement,
by executing and delivering this Amendment, the Company and each Investor has
approved this Amendment.

     NOW, THEREFORE, in consideration of the premises and the mutual covenants
contained in this Amendment and for other good and valuable consideration, the
receipt and sufficiency of which are hereby acknowledged, the parties hereto
agree as follows:

     1.    AMENDMENT OF INVESTOR RIGHTS AGREEMENT.

     (i)   The Investor Rights Agreement is hereby amended by deleting the
preamble in its entirety and by substituting in lieu thereof the following:

     "THIS AMENDED AND RESTATED INVESTOR RIGHTS AGREEMENT (this "AGREEMENT")
dated as of December 13, 2002, is by and among Synta Pharmaceuticals Corp., a
Delaware corporation (the "COMPANY"), Robert A. Day and Mountain Trail
Investments, LLC,

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(singly, a "DAY INVESTOR", and collectively, the "DAY INVESTOR"), Keith R.
Gollust, Gollust Trust II, and Wyandanch Partners, L.P. (singly, a "GOLLUST
INVESTOR", and collectively, the "GOLLUST INVESTOR") and Bruce Kovner and
Cxsynta LLC, an affiliate of Caxton Corporation (singly, a "CAXTON INVESTOR",
and collectively, the "CAXTON INVESTOR") (each an "INVESTOR" and, collectively,
the "INVESTORS")."

     (ii)  The Investor Rights Agreement is hereby amended by deleting Sections
1(d), (e), (h), (q), (r), (t), (u) and (v) in their entirety and by substituting
in lieu thereof the following:

           "(d)    The term "COMPANY INDEMNIFIED PARTIES" has the meaning set
     forth in SECTION 2.7(a) hereof."

           "(e)    [Intentionally omitted.]"

           "(h)    The term "HOLDER" means any person owning or having the right
     to acquire Registrable Securities, or any assignee thereof, in accordance
     with SECTION 2.9 hereof."

           "(q)    The term "REGISTRABLE SECURITIES" means (i) any shares of
     Common Stock held by an Investor (ii) any shares of capital stock of the
     Company acquired by an Investor (or any transferee of an Investor) after
     the date hereof pursuant to the Stockholders' Agreement and (iii) any
     Common Stock issued as (or issuable upon the conversion or exercise of any
     warrant, right or other security) a dividend or other distribution with
     respect to or because of stock splits, stock dividends, reclassifications,
     recapitalizations, or similar events, or in exchange for, or in replacement
     of the shares referenced in (i) and (ii) above, excluding in all cases,
     however, any Registrable Securities sold by a person in a transaction in
     which his, her or its rights under SECTION 2 hereof are not assigned.
     Registrable Securities shall exclude any shares which (A) have been
     registered under the Securities Act pursuant to an effective registration
     statement filed thereunder and disposed of in accordance with the
     registration statement covering them, or (B) may be publicly sold pursuant
     to and in compliance with SEC Rule 144 in any ninety (90) day period,
     provided that such shares shall not be excluded if (x) the number of shares
     proposed to be sold by such Investor is larger than the number of shares
     that may be sold in any single 90-day period pursuant to Rule 144 or (y)
     such Investor believes in good faith that a sale pursuant to Rule 144 will
     be less advantageous to it than a sale pursuant to SECTIONS 2.1, 2.2 or
     2.3."

           "(r)    The term "REQUESTING HOLDERS" has the meaning set forth in
     SECTION 2.1(a) hereof."

           "(t)    The term "SELLING HOLDER" has the meaning set forth in
     SECTION 2.2(a) hereof."

           "(u)    The term "SELLING HOLDER INDEMNIFIED PARTIES" has the meaning
     set forth in SECTION 2.7(b) hereof."

           "(v)    The term "VIOLATION" has the meaning set forth in
     SECTION 2.7(a) hereof."

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     (iii) The Investor Rights Agreement is hereby amended by deleting Section 2
in its entirety and by substituting in lieu thereof the following:

"2.  Registration Rights. The Company covenants and agrees as follows:

     2.1   DEMAND REGISTRATION.

           (a)     Commencing upon the expiration of any lock-up agreement that
the Holders have entered into with the underwriters in connection with an
Initial Offering pursuant to SECTION 2.10, subject to the limitations set forth
in this SECTION 2, the Holders of not less than 60% of the then outstanding
Registrable Securities (the "REQUESTING HOLDERS") may at any time give to the
Company a written request for the registration (a "DEMAND REGISTRATION") by the
Company under the Act of all or any part of the Registrable Securities held by
such Requesting Holders. Within 15 business days after the receipt by the
Company of any such written request, the Company will give written notice of
such request to all Holders of Registrable Securities.

           (b)     Subject to the limitations set forth in this SECTION 2, after
the receipt of a written request for a Demand Registration, (i) the Company will
be obligated to include in such Demand Registration all Registrable Securities
with respect to which the Company receives from Holders of Registrable
Securities the written requests of such Holders for inclusion in such Demand
Registration, within 30 days after the date on which the Company gives to all
Holders a written notice of registration request pursuant to SECTION 2.1(a), and
(ii) the Company shall file a registration statement covering all such
Registrable Securities as soon as practicable after receipt of the written
requests of such Holders for inclusion in such Demand Registration, and shall
use its commercially reasonable efforts to effect the registration of all such
Registrable Securities. All written requests made by Holders of Registrable
Securities pursuant to this SECTION 2.1(b) will specify the number of
Registrable Securities to be registered and will also specify the intended
method of disposition thereof. If the Requesting Holders intend to distribute
the Registrable Securities by means of an underwriting, they shall so advise the
Company in their request. The underwriter shall be reasonably acceptable to the
Company.

           (c)     The registration statement filed pursuant to any Demand
Registration pursuant to this SECTION 2.1 may, subject to the limitations set
forth in this SECTION 2, include other securities of the Company which are held
by persons other than the Holders who, by virtue of agreements with the Company,
are entitled to include their securities in any such registration.

           (d)     The Company shall not be required to effect any Demand
Registration of any Registrable Securities pursuant to this SECTION 2.1 if the
anticipated aggregate offering price, net of underwriting discounts and
commissions, of the Registrable Securities will not equal or exceed fifteen
million dollars ($15,000,000).

           (e)     The Company shall not be required to effect more than two (2)
Demand Registrations pursuant to this SECTION 2.1.

           (f)     The Company will not be obligated to effect any Demand
Registration of any Registrable Securities pursuant to this SECTION 2.1 during
the period commencing on the date falling 90 days prior to the Company's
estimated date of filing of, and ending on the date 180

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days following the effective date of, any registration statement pertaining to
any registration initiated by the Company, for the account of the Company (other
than with respect to securities registered solely in connection with
acquisitions, employee benefit plans, and the like), if the written request of
the Requesting Holders for such Demand Registration pursuant to SECTION 2.1(a)
hereof is received by the Company after the Company has commenced an
underwritten registration initiated by the Company and provides reasonable
evidence that it commenced activities directly related to such filing before
receiving the written request of the Holders; PROVIDED, HOWEVER, that the
Company will use its commercially reasonable efforts in good faith to cause any
such registration statement to be filed and to become effective as expeditiously
as is reasonably possible.

           (g)     The Company will not be obligated to effect any Demand
Registration of any Registrable Securities pursuant to this SECTION 2.1 for not
more than a 120-day period, if: (i) in the good faith judgment of the Board of
Directors of the Company, such registration would be seriously detrimental to
the Company and the Board of Directors of the Company concludes, as a result,
that it is essential to defer the filing of such registration statement at such
time, and (ii) the Company shall furnish to such Holders a certificate signed by
the Chief Executive Officer of the Company stating that in the good faith
judgment of the Board of Directors of the Company, it would be seriously
detrimental to the Company for such registration statement to be filed in the
near future and that it is, therefore, essential to defer the filing for a
period of not more than 120 days after receipt of the request of the Requesting
Holders; and FURTHER PROVIDED, that the Company shall not defer its obligation
in this manner more than once in any twelve-month period.

           (h)     If the managing underwriters in any Demand Registration
advise the Company that the number of securities proposed to be included in such
registration exceeds, in the opinion of the managing underwriters of such
registration in light of marketing factors, the number of securities to which
such registration should be limited (the "UNDERWRITERS' MAXIMUM NUMBER"), then:
(i) the Company will be obligated to include in such registration that number of
Registrable Securities requested by Holders to be included in such registration
as does not exceed the Underwriters' Maximum Number, and such number of
Registrable Securities will be allocated PRO RATA among such Holders on the
basis of the number of Registrable Securities held by each such Holder; (ii) if
the Underwriters' Maximum Number exceeds the number of Registrable Securities
requested by Holders to be included in such registration, then the Company will
be entitled to include in such registration that number of securities as has
been requested by the Company to be included in such registration for the
account of the Company and that is not greater than such excess; and (iii) if
the Underwriters' Maximum Number exceeds the sum of the number of Registrable
Securities that the Company is obligated under clause (i) above to include in
such Demand Registration plus the number of securities that the Company proposes
to offer and sell for its own account in such registration, then the Company may
include in such registration that number of other securities as security holders
other than Holders may have requested be included in such registration and that
is not greater than such excess, and such number of excess securities will be
allocated PRO RATA among such security holders other than the Holders on the
basis of the number of such securities requested to be included in such
registration by each such security holder. Neither the Company nor any of its
other security holders will be entitled to include any securities in any
underwritten Demand Registration unless the Company or such security holders
(as the case may be) agree in writing to sell such securities

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on the same terms and conditions as apply to the Registrable Securities held by
Holders to be included in such Demand Registration.

     2.2   PIGGYBACK REGISTRATION.

           (a)     At any time subsequent to the expiration of any lock-up
agreement that the Holders have entered into with the underwriters in connection
with an Initial Offering pursuant to SECTION 2.10, if (but without any
obligation to do so) the Company proposes to register (including for this
purpose a registration effected by the Company for stockholders other than the
Holders) any of its stock or other securities under the Act (other than a
registration statement on Form S-8 or Form S-4, or their successors, or any
registration statement effected solely to implement an employee benefit plan or
covering only securities proposed to be issued in exchange for securities or
assets of another corporation), the Company shall, at such time, promptly give
each Holder written notice of such registration. Upon the written request of
each Holder (a "SELLING HOLDER") received within 30 days after the date on which
the Company gives such notice in accordance with the provisions hereof, the
Company shall, subject to the provisions of this SECTION 2, use all reasonable
efforts to cause to be registered under the Act all of the Registrable
Securities that each such Holder has requested to be registered.

           (b)     The Company shall have the right to terminate or withdraw any
registration initiated by it under this SECTION 2.2 prior to the effectiveness
of such registration whether or not any Holder has elected to include securities
in such registration. The expenses of such withdrawn registration shall be borne
by the Company in accordance with SECTION 2.6 hereof.

           (c)     In connection with any offering involving an underwriting of
shares of the Company's capital stock, the Company shall not be required under
this SECTION 2.2 to include any of the Holders' securities in such underwriting
unless they accept the terms of the underwriting as agreed upon between the
Company and the underwriters selected